Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[CH3:21])=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1(O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1=C(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Yield: 94.9 %

Procedure:
A suspension of tert-butyl 4-(4-chlorophenyl)-4-hydroxy-3-methylpiperidine-1-carboxylate (5.5 g, 16.88 mmol) in concentrated HCl (15 mL, 180 mmol) was stirred until a homogeneous solution was observed. The reaction was then heated to reflux and stirred overnight. The mixture was cooled to 0° C. and treated with the careful, portion-wise addition of solid sodium hydroxide until a pH of ˜13 was achieved. The biphasic mixture was extracted 5× with ethyl acetate, and the combined organic phases were washed with a small amount of brine, dried over sodium sulfate, and concentrated in-vacuo to 3.3 g of a colorless oil. The oil was dissolved in THF (50 mL), and the resulting solution was treated with BOC-anhydride (4.67 mL, 20.13 mmol). The reaction was stirred for two days at room temperature. After this time, the mixture was concentrated in vacuo, and the resulting residue was purified over a 330 g silica gel column, eluting at 100 mL/min with a 0% to 15% ethyl acetate/hexanes gradient followed by 15% ethyl acetate/hexanes to yield the title compound (4.93 g, 16.02 mmol, 88% yield) as a colorless solid. The product isolated contained 15% of tert-butyl 4-(4-chlorophenyl)-5-methyl-5,6-dihydropyridine-1(2H)-carboxylate, resulting from a byproduct in the previous step. The material was used as-is. MS (ESI+)=252.2 (M+tert-Bu)+.
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])[CH:5]=[C:4]([C:18]2[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=2)[CH:3]=1.[NH2:24][C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[C:4]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[CH:3]=[C:2]([NH:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: C[C@H](Nc1cc(-c2cnn(C)c2)cc(Cl)n1)c1ccc(F)cc1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1cc(-c2cnn(C)c2)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
235 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)pyridine-2-amine, 74 mg of 2-aminopyrazine, 68 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 95 mg of sodium t-butoxide and 37 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 1.5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution 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 204 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-4-(1-methyl-1H-pyrazol-4-yl)-N6-(pyrazin-2-yl)pyridine-2,6-diamine as pale yellow powder. The obtained compound was dissolved in ethanol, and an equivalent of 1N hydrochloric acid was added thereto, and then the solvent was removed to obtain the objective, compound as pale yellow powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=[O:7].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1.CCN(CC)CC.CO>C(COC)OC>[O:7]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:8]([C:20](=[O:21])[NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:23])[F:22])[CH:14]=1)[C:9]#[N:10]
Reactant: N#CCC(=O)c1ccc[nH]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: COCCOC
Solvent: CO
Solvent: CCN(CC)CC
Product: N#CC(C(=O)Nc1cccc(C(F)(F)F)c1)C(=O)c1ccc[nH]1

Procedure:
Reaction of 2.0 g of 2-pyrroloylacetonitrile with 3.0 g of 3-(trifluoromethyl)-phenyl isocyanate in the presence of 1.8 g of Et3N in 25 ml of glyme similarly to the previous examples and recrystallization of the crude product from methanol gives β-oxo-α-(3-trifluoromethylphenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile, m.p. 210°-212°.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.[H+].[B-](F)(F)(F)[F:21].N([O-])=O.[Na+].NC(N)=O>O>[C:16]([C:13]1[CH:14]=[CH:15][C:9]2[CH:8]=[CH:7][C:6]3[CH:18]=[C:2]([F:21])[CH:3]=[CH:4][C:5]=3[S:11][C:10]=2[CH:12]=1)#[N:17]
Reactant: N#Cc1ccc2c(c1)Sc1ccc(N)cc1C=C2
Reactant: F[B-](F)(F)F
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: N#Cc1ccc2c(c1)Sc1ccc(F)cc1C=C2
Reaction time: 4 h

Procedure:
Suspend 6 gm. of the 3-cyano-8-aminodibenzo[b,f]thiepine from Example 18, Step 1, in 15 ml. of 50% fluoboric acid (HBF4) and 15 ml. of water. Cool the mixture to 3°-5° C. and slowly add 18 ml. of 10% sodium nitrite. Stir in the cold for 4 hours and add urea to destroy the excess sodium nitrite. Separate the solids by filtration and wash with cold 5% fluoboric acid followed by cold water and then ether. Air dry. Suspend the diazonium fluoroborate in 300 ml. of xylene and reflux for 2 hours with stirring. Filter and evaporate the filtrate to dryness. Triturate with ether to obtain the title product (m.p., 146°-148° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]2[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][C:25]([C:23]4[CH:24]=[C:19]([N:16]5[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]5)[N:20]=[C:21]([NH2:35])[N:22]=4)=[CH:26][CH:27]=3)[CH2:32]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)c3ccc(Cl)cc3)CC4)nc(N)n2)CC1
Reaction time: 0.5 h

Procedure:
4-Chlorobenzoic acid chloride (4.4 μL, 0.034 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (16 μL, 0.12 mmol) in tetrahydrofuran (0.3 mL). After 30 min, the mixture was purified by RP-LCMS (pH=10) to afford the desired products. Analytic LCMS (M+H)+: m/z=463.3/465.3
Reaction SMILES: N[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[OH-:15].[Na+]>>[CH3:12][O:11][C:7]1[C:6]2[C:2](=[O:15])[NH:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2c1C(N)=NS2(=O)=O
Reactant: [OH-]
Agent: [Na+]
Product: COc1cccc2c1C(=O)NS2(=O)=O

Procedure:
2.5 gm (11.8 mmols) of 3-amino-4-methoxy-1,2-benzoisothiazole-1,1-dioxide were reacted with sodium hydroxide analogous to Example 4. The reaction mixture was acidified, whereby 4-methoxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide was obtained, which was subsequently heated at 200°-205° C. with 20 gm of pyridine hydrochloride. After cooling, the reaction mixture was extracted several times with boiling benzene, the residue was dissolved in water, and the aqueous solution was again extracted with boiling benzene. The combined benzene phases were dried and evaporated in vacuo. The residue was recrystallized from water, yielding 1.35 gm (57.5% of theory) of 4-hydroxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C([N:15](CC)CC)C.C(OC(Cl)=O)C(C)C.N>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH2:15])=[O:6]
Reactant: CCN(CC)CC
Reactant: COc1ccc(C(=O)O)cc1F
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(N)=O)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 3-fluoro-4-methoxybenzoic acid (400 mg, 2.4 mmol) and triethylamine (560 μl, 3.5 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was added isobutylchloroformate (320 μl, 2.4 mmol), and the mixture was stirred at 0° C. for 1 hour. The solution was warmed to room temperature and was saturated with ammonia gas, then stirred for 15 hours at room temperature. The mixture was diluted with ethyl acetate, then washed with 20% aqueous citric acid, saturated aqueous sodium bicarbonate, and brine, then dried over anhydrous sodium sulfate. Filtration and concentration afforded 280 mg, 1.7 mmol (70%) of 3-fluoro-4-(methyloxy)benzamide. MS (EI) for C8H8FNO2: 170 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([O:8][CH2:9][CH2:10][OH:11])[C:3]=1[C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1.[H-].[Na+].[Cl:23][C:24]1[CH:25]=[N:26][C:27](S(C)(=O)=O)=[N:28][CH:29]=1.[Cl-].[NH4+]>O1CCCC1>[O:16]1[C:15]2[CH:19]=[CH:20][C:12]([C:3]3[C:4]([O:8][CH2:9][CH2:10][O:11][C:27]4[N:28]=[CH:29][C:24]([Cl:23])=[CH:25][N:26]=4)=[N:5][N:6]([CH3:7])[C:2]=3[NH2:1])=[CH:13][C:14]=2[O:18][CH2:17]1
Reactant: Cn1nc(OCCO)c(-c2ccc3c(c2)OCO3)c1N
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a −78° C. cooled solution of 2-{[5-amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-yl]oxy}-1-ethanol (710 mg) (Preparation 45) in anhydrous tetrahydrofurane (25 ml) under an atmosphere of nitrogen, was added sodium hydride (60% dispersion in oil, 113 mg) and the mixture was stirred for 10 minutes at this temperature before 5-chloro-2-(methylsulfonyl)pyrimidine (543 mg) was added in one portion and the mixture was stirred overnight at room temperature. The TLC indicated an incomplete reaction so the mixture was cooled to −78° C. and another portion of sodium hydride (60% dispersion in oil, 100 mg) was added. The mixture was stirred for 12 h at room temperature. Again, the TLC indicated an incomplete reaction. The mixture was cooled again to −78° C. and sodium hydride (60% dispersion in oil, 100 mg) was added. After 10 minutes at this temperature, 5-chloro-2-(methylsulfonyl)pyrimidine (200 mg) was added in one portion. The reaction was stirred overnight at room temperature. An aqueous saturated solution of ammonium chloride (1 ml) was carefully added before the reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of water (20 ml) and dichloromethane (20 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2×20 ml). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 30 g) eluted with dichloromethane:methanol (95:5) yielding the title compound as a colourless oil (910 mg).
Reaction SMILES: [OH:1][CH:2]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=1)=[O:6].[N:18]1([C:24]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[C:33]([F:36])([F:35])[F:34])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[OH:1][CH:2]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:21]2[CH2:22][CH2:23][N:18]([C:24](=[O:25])[C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[C:33]([F:36])([F:35])[F:34])[CH2:19][CH2:20]2)=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(C)(C)C(O)CNC(=O)c1ccc(Cl)nn1
Reactant: O=C(c1cc(F)ccc1C(F)(F)F)N1CCNCC1
Product: CC(C)(C)C(O)CNC(=O)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-hydroxy-3,3-dimethylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(5-fluoro-2-trifluoromethylphenyl)methanone, the title compound was obtained as a brown solid (51% yield). m.p.: 186-189° C. 1H NMR (300 MHz, CDCl3) δ8.20, 8.04, 7.75, 7.22, 7.07, 6.98, 4.06-3.98, 3.91-3.71, 3.47-3.23, 2.45, 0.96. 13C NMR (75 MHz, CDCl3) δ 166.3, 164.1, 160.1, 160.0, 130.1, 127.2, 116.9, 116.6, 115.0, 114.7, 112.4, 79.4, 46.4, 44.5, 44.3, 41.9, 41.3, 34.4, 25.7. MS (ES+) m/z 498 (M+1).
Reaction SMILES: ClC1C=CC(OCC2C=CC=CC=2)=C(C2C=CC=CC=2[B:14]([OH:16])[OH:15])C=1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=1[O:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1>>[F:50][C:47]1[CH:48]=[CH:49][C:44]([CH2:43][O:42][C:33]2[CH:34]=[CH:35][C:36]([C:38]([F:41])([F:40])[F:39])=[CH:37][C:32]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[B:14]([OH:16])[OH:15])=[CH:45][CH:46]=1
Reactant: OB(O)c1ccccc1-c1cc(Cl)ccc1OCc1ccccc1
Reactant: Fc1ccc(COc2ccc(C(F)(F)F)cc2-c2ccccc2Br)cc1
Product: OB(O)c1ccccc1-c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1

Procedure:
Prepared as for {5′-chloro-2′-[(phenylmethyl)oxy]-2-biphenylyl}boronic acid but using 2′-bromo-2-{[(4-fluorophenyl)methyl]oxy}-5-(trifluoromethyl)biphenyl instead of 2′-bromo-5-chloro-2-[(phenylmethyl)oxy]biphenyl. LC/MS t=3.63, [MH−] 389.0
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:18]Br)=[C:13]([CH2:16]Br)[CH:14]=2)[C@H:9]([N:20]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2].[OH-:41].[Na+]>C1C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][O:41][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([N:20]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(CBr)c(CBr)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)N1c2cc3c(cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C)COC3
Temperature: 80 °C
Yield: 25 %

Procedure:
To a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-bis-bromomethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 27B) (50 mg, 0.71 mmol) in 0.25 ml benzene was added benzyl tri-n-butylammonium chloride (23 mg, 0.71 mmol) and 30% NaOH (28 μl). The reaction mixture was heated to 80° C. for 4 hours. The mixture was diluted with 0.75 ml ethyl acetate. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (2×0.25 ml). The combined extracts were dried (MgSO4), filtered and concentrated. The crude material was chromatographed on silica gel (25% ethyl acetate:hexane) to afford the title product (10 mg, 25%). MS m/z 561 (M+); 1H NMR (CDCl3) δ3.85 (s, 3H), 6.85 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1nc(-c2ccccc2)cc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc(-c2ccccc2)cc2ccccc12
Reaction time: 48 h
Yield: 38.5 %

Procedure:
A mixture of 1-methyl-3-phenylisoquinoline (21 g), N-bromosuccinimide (30.6 g) and benzoyl peroxide (1 g) in carbon tetrachloride (730 cc) is brought to boiling for 48 hours. After being cooled, the mixture is filtered and the filtrate evaporated to dryness under reduced pressure. The residue is chromatographed on silica gel with a toluene/methanol (98:2 by volume) mixture as eluant. After crystallization in isopropyl ether, 1-bromomethyl-3-phenylisoquinoline (11 g), m.p. 84° C., is obtained.
Reaction SMILES: [CH3:1][CH:2]([CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[CH:10]=1)[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].I>>[CH3:1][CH:2]([CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)[CH2:7][CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CCC(c1cccc(OC)c1)C(C)C(=O)O
Agent: I
Product: CCC(c1cccc(O)c1)C(C)C(=O)O
Temperature: 25 °C

Procedure:
The steps are: add 2-methyl-3-(3-methoxyphenyl) valeric acid into a reaction flask, add hydroiodic acid, and perform heating and reflux for 12 hours; detect the reaction process by TLC; after that, cool the resultant to the room temperature, pour it into an alkaline solution to make the pH become 9, perform extraction by ethyl acetate, reversely adjust the pH of the water layer to about 3.0 after the water layer is separated out, and add ethyl acetate for extraction; and dry the ethyl acetate extracting solution by anhydrous magnesium sulphate, and recycle the solvent by decompression to obtain a light yellow liquid, 2-methyl-3-(3-hydroxyphenyl) valeric acid.
Reaction SMILES: N[CH:2]1[C:18](=[O:19])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=[O:23].Cl>C(N(CC)CC)C>[O:23]=[C:2]1[C:18](=[O:19])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[C:6]([CH3:9])[CH2:7][S:8][C@H:3]12
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2SC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(=O)[C@H]2SC1

Procedure:
2,2,2-Trichloroethyl 7-amino-3-methyl-3-cephem-4-carboxylate, trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid were reacted in the same manners as those of Examples 1-4 to give 2,2,2-trichloroethyl 7-oxo-3-methyl-3-cephem-4-carboxylate.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]#[N:14])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]#[N:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C#N)c2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: N#Cc1ccc(O)c2ccccc12

Procedure:
Ten grams of 1-methoxy-4-naphthonitrile was dissolved in 270 ml of benzene, 15.4 grams of aluminum chloride was added thereto, and the mixture was heated to reflux for eighteen hours with stirring. After the reaction was completed, the reaction mixture was partitioned between ethyl acetate and water, the ethyl acetate layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated to afford crude 1-hydroxy-4-naphthonitrile. This was dissolved in 250 ml of dimethyl formamide, 3.39 grams of sodium hydride (50%) was added thereto little by little with ice, cooling and stirring, then 10.21 grams of benzyl bromide was added, and the mixture was stirred for three hours at room temperature. The reaction mixture was subjected to a partition between benzene and water, the benzene layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated therefrom followed by recrystallization of the residue to give 1-benzyloxy-4-naphthonitrile, pale yellow needles, yield 11.85 grams. Nuclear magnetic resonance spectra (CDCl3) δ: 5.20 (2H, s, --CH2 --Ph).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[CH:6][O:5][CH:4]=1.N1C=CC=CC=1.[C:14](Cl)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O1CCCC1>[C:14]([O:1][CH2:2][C:3]1[CH:7]=[CH:6][O:5][CH:4]=1)(=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: OCc1ccoc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCC(=O)OCc1ccoc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-hydroxymethylfuran (1.01 g., 10.3 mmol) and pyridine (0.87 g., 10.3 mmol) in 30 ml dry tetrahydrofuran at 0° under argon was added lauroyl chloride (2.36 g., 10.8 mmol). This solution was allowed to warm to room temperature, during which time a white precipitate formed. After one hour, the mixture was filtered and the solution partitioned between ethyl ether and a 5% ammonium chloride solution. The organic portion was washed twice with 5% sodium bicarbonate solution, three times with aqueous cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil. This material was further purified by flash chromatography (silica, 5% ethyl ether/petroleum ether) to give the desired ester.
Reaction SMILES: [N:1]1([C:7](=[O:26])[CH2:8][CH2:9][N:10]2[C:22]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[N:12]=[C:11]2[CH2:23][CH2:24][CH3:25])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:50]>>[N:1]1([C:7](=[O:26])[CH2:8][CH2:9][N:10]2[C:22]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[N:15]=[C:14]([NH2:50])[C:13]=3[N:12]=[C:11]2[CH2:23][CH2:24][CH3:25])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(=O)N1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCC(=O)N1CCOCC1

Procedure:
1-(3-Morpholin-4-yl-3-oxopropyl)-2-propyl-1H-imidazo[4,5-c]quinoline (5.2 g, 15 mmol) was treated with mCPBA (7.64 g, 44.3 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (3.79 g, 19.9 mmol) according to the method described in Part D of Example 8. The crude product was purified by column chromatography on silica gel (eluting with 95:5 dichloromethane:methanol) followed by recrystallization from methanol:dichloromethane to provide 0.358 g of 1-(3-morpholin-4-yl-3-oxopropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as yellow needles, mp 172-173° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:39])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:38])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[CH:32][NH:33]3)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:12][NH2:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[S:81]1[CH:85]=[CH:84][CH:83]=[C:82]1[C:86](O)=[O:87]>CN(C=O)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:39])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:38])[NH:27][CH2:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[CH:32][NH:33]3)=[CH:20][C:21]=1[C:22]([F:24])([F:25])[F:23])=[O:16])[CH2:12][NH:13][C:86]([C:82]1[S:81][CH:85]=[CH:84][CH:83]=1)=[O:87]
Reactant: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C(F)(F)F
Reactant: O=C(O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc3[nH]ccc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a solution of (S)-3-Amino-2-({5-[(1H-indol-4-ylmethyl)-carbamoyl]-3-trifluoromethyl-thiophene-2-carbonyl}-amino)-propionic acid methyl ester trifluoro-acetic acid salt (0.32 g, 0.49 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.20 mL, 1.47 mmol), HBTU (0.28 g, 0.74 mmol), HOBT (0.079 g, 0.59 mmol), and 2-Thiophenecarboxylic acid (0.069 g, 0.54 mmol). The mixture was stirred at room temperature 2 h, treated with EtOAc (100 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (0-80% EtOAc in hexane) to give 0.172 g (61%) colorless oil product. MS m/e 579.0 (M+H+).