Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:9][NH:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](\[CH2:30][CH3:31])/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1>>[CH2:1]([NH:6][C:7](=[O:8])[N:10]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](\[CH2:30][CH3:31])/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN=C=O
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)c2)cc1)CC
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)OCC)cc2)c1
Temperature: 100 °C
Yield: 98.4 %

Procedure:
136 μL (1.0 mmol) of pentyl isocyanate are added to 213 mg (0.7 mmol) of ethyl 2-[1-(3′-methylaminobiphenyl-4-yl)meth-(E)-ylidene]butyrate. The reaction mixture is heated at 100° C. in an Emrys Optimizer microwave oven for 20 minutes. The residue is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 291 mg (100%) of ethyl 2-[1-[3′-(3-pentyl-1-methylureido)biphenyl-4-yl]meth-(E)-ylidene]butyrate are obtained in the form of a yellowish oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=1.Cl.[CH3:25][NH:26][CH3:27].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:22])[N:26]([CH3:27])[CH3:25])[CH:15]=1
Reactant: O=C(O)c1cccc(C(=O)Nc2cccc3cc(Br)cnc23)c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cccc(C(=O)Nc2cccc3cc(Br)cnc23)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
A mixture of 3-bromo-8-(3-carboxybenzoylamino)quinoline (200 mg), dimethylamine hydrochloride (65.9 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (100 mg) and 1-hydroxybenzotriazole (109 mg) in dimethylformamide (3 ml) was stirred for 3 hours at ambient temperature. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate) and recrystallized from ethanol to give 3-bromo-8-[3-(dimethylcarbamoyl)benzoylamino]quinoline (120 mg) as pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([NH:14][C:15](=[CH2:20])[C:16]([O:18][CH3:19])=[O:17])(=O)C>>[CH3:10][C:8]1[CH:9]=[C:2]2[C:3](=[CH:6][CH:7]=1)[CH:4]=[N:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20]2
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: Cc1ccc(C=O)c(Br)c1
Product: COC(=O)c1cc2cc(C)ccc2cn1
Yield: 50 %

Procedure:
methyl 6-methyl-isoquinoline-3-carboxylate was prepared using the procedure described in example 12A: 2-bromo-4-methylbenzaldehyde was reacted with methyl 2-acetamidoacrylate at 110° C. for 18 hours to yield methyl 6-methyl-isoquinoline-3-carboxylate (50%) as brown solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[CH3:8][N:9]([CH3:13])[C:10](Cl)=[O:11].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C(C)=CC=CC=1>[CH3:8][N:9]([CH3:13])[C:10]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1)=[O:11]
Reactant: Cc1csc(N)n1
Reactant: CN(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: Cc1csc(NC(=O)N(C)C)n1
Yield: 93.5 %

Procedure:
A mixture of 2-amino-4-methylthiazole (1.14 g), N,N-dimethylcarbamoyl chloride (1.29 g), aluminum chloride (1.60 g), and xylene (40 ml) is refluxed for 20 hours. The reaction mixture is worked up as in Example 1, whereby 1,1-dimethyl-3-(4-methyl-2-thiazolyl)urea (1.73 g) is obtained. Yield is 93.5%. Melting point is 97° to 98° C. (Pure product is recrystallized from ether/petroleum ether).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Product: Cc1cc(NS(=O)(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)on1
Yield: 78 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(4-trifluoromethylphenyl)benzenesulfonamide was prepared in the same manner as described in Example 14b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and 4-trifluoromethylbenzeneboronic acid resulting in the final product in a 78% yield, m.p. 150-153° C. The product was recrystallized using an acetonirile and water mixture.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]3)[CH:12]=[CH:13][CH:14]=2)O1.Cl[C:31]1[C:39]2[C:34](=[CH:35][N:36]=[C:37]([C:40]3[CH:41]=[N:42][N:43]([CH3:45])[CH:44]=3)[CH:38]=2)[N:33]([CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[N:32]=1>>[CH3:45][N:43]1[CH:44]=[C:40]([C:37]2[CH:38]=[C:39]3[C:31]([C:9]4[CH:10]=[C:11]([N:15]5[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:16]5)[CH:12]=[CH:13][CH:14]=4)=[N:32][N:33]([CH:46]4[CH2:51][CH2:50][CH2:49][CH2:48][O:47]4)[C:34]3=[CH:35][N:36]=2)[CH:41]=[N:42]1
Reactant: Cn1cc(-c2cc3c(Cl)nn(C4CCCCO4)c3cn2)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)C1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC[C@@H](NC(=O)OC(C)(C)C)C5)c4)nn(C4CCCCO4)c3cn2)cn1
Yield: 60 %

Procedure:
Following the Suzuki coupling procedure in Example 172, (R)-tert-butyl 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-3-ylcarbamate and 3-chloro-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted to give tert-butyl (3R)-1-(3-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazo-lo[3,4-c]pyridin-3-yl)phenyl)piperidin-3-ylcarbamate as a solid (60%). 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.93 (s, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 6.73 (d, J=8.4 Hz, 1H), 5.90-5.83 (m, 1H), 4.09-4.00 (m, 2H), 3.97 (s, 3H), 3.88-3.76 (m, 2H), 3.67 (s, 1H), 3.52 (s, 1H), 3.17 (s, 1H), 3.03 (s, 1H), 2.64-2.52 (m, 1H), 2.17 (d, J=10.1 Hz, 2H), 2.09-1.99 (m, 1H), 1.84-1.70 (m, 5H), 1.65-1.54 (m, 1H), 1.41 (s, 9H). LC/MS: m/z 558.2 [M+1].
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:25]([N:27]1[CH2:32][CH2:31][C:30]2([C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]([CH3:41])=[CH:33]2)[CH2:29][CH2:28]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C)C)(C)C>C(O)C.[C].[Pd]>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:25]([N:27]1[CH2:28][CH2:29][C:30]2([C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]([CH3:41])[CH2:33]2)[CH2:31][CH2:32]1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=CC2(CCN(C(=O)c3cnc4c(C(=O)NS(C)(=O)=O)cnn4c3NCc3ccccc3)CC2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CC1CC2(CCN(C(=O)c3cnc4c(C(=O)NS(C)(=O)=O)cnn4c3NCc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.5 %

Procedure:
N-[7-Benzylamino-6-(3-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]methanesulfonamide (0.035 g, 0.061 mmol) obtained in Example 111, step 3 was dissolved in ethanol (2.0 ml), 10% palladium-carbon (0.079 g, 0.382 mmol) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was filtered through celite and washed with chloroform, and the filtrate was concentrated under reduced pressure to give a residue. Diisopropyl ether was added to the residue and the precipitated crystals were collected by filtration to give the title compound (0.011 g, 32%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C([O-])(=[O:16])C.[Na+].CN(C)C=O>O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][OH:16]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc2ccccc2n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 2-chloromethylquinoline hydrochloride (21.4 g), sodium acetate (32.8 g) and N,N-dimethylformamide (200 ml) was stirred at 60° C. overnight. After cooling, the reaction solution was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. A mixture of the residue, 4N aqueous sodium hydroxide solution (50 ml), tetrahydrofuran (100 ml) and methanol (100 ml) was stirred at room temperature for 1 hour, and poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-quinolylmethanol (14.0 g, yield 88%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 68–69° C.
Reaction SMILES: [Na].Cl.[C:3](=[NH:8])(OCC)[CH3:4].[CH3:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][CH:12]=1>C(O)C>[NH:8]=[C:3]([NH:18][NH:17][C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:20][CH:19]=1)[CH3:4]
Reactant: CCOC(C)=N
Reactant: COc1ccc(C(=O)NN)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: COc1ccc(C(=O)NNC(C)=N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.6 g (0.20 mol) sodium in 200 mL ethanol are combined at ambient temperature with a solution of 25 g (0.20 mol) ethyl acetimidate hydrochloride in 200 mL ethanol. The sodium chloride precipitated is suction filtered and 33.2 g (0.20 mol) 4-methoxybenzoic acid hydrazide are added to the filtrate. The reaction mixture is stirred overnight at ambient temperature and then cooled. The precipitate formed is separated off and washed with ethanol and diethyl ether. Yield: 33.6 g (81%); melting range=179-181° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: CN(C)CCCO
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc(O)cc2)[nH]c1-c1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CCCOc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(F)cc3)[nH]2)cc1

Procedure:
5-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 3-dimethylaminopropanol, triphenyl-phosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 5-(4-fluorophenyl)-2-(4-(3-dimethylaminopropyloxy)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:19]Br)=[O:5])[CH3:2].[CH2:21]([O:23][C:24](=[O:34])[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:22].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][C:7]=1[CH2:19][N:26]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N(C)c2ccccc2)nc1CBr
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1nc(N(C)c2ccccc2)sc1C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 49.6 %

Procedure:
A mixture of 4-bromomethyl-2-(methyl-phenyl-amino)-thiazole-5-carboxylic acid ethyl ester (974 mg, 2.75 mmol), tert-butoxycarbonylamino-acetic acid ethyl ester (559 mg, 2.75 mmol) and sodium hydride (60% in mineral oil, 132 mg, 3.30 mmol) in anhydrous dimethylformamide (10 mL) was stirred at 0° C. for two hours and room temperature for 18 h before it was quenched with brine. It was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (652 mg): MS: (+) m/z 500.0 (M+Na+).
Reaction SMILES: [CH:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:14]1[C:15]2[CH:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[CH3:32])[C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[N:19]=1>CN(C=O)C.O>[CH:1]1([O:10][C:14]2[C:15]3[CH:24]=[CH:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=4[CH3:32])[C:16]=3[C:17](=[O:21])[N:18]([CH3:20])[N:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Reactant: OC1CCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccc3c(OC4CCc5ccccc54)nn(C)c(=O)c32)c(C)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
To a solution of 1-indanol (60 mg, 0.45 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 18 mg, 0.45 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-(2,4-dimethylphenyl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (43.2 mg, 0.15 mmol). The mixture was stirred at 60° C. for 3 hours, then diluted with water (30 ml) and extracted with ethyl acetate (30 ml×2). The extract were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (10:1) to give 28 mg (48%) of the title compounds as an oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:58]1[CH:67]=[CH:66][C:65]([OH:68])=[C:64]2[C:59]=1[CH:60]=[CH:61][C:62](=[O:69])[NH:63]2)[CH2:10][NH:11]CCCC#CC1C=C(NC(C2C=C(S(C3C=C4C(=C(C)C=3)N=CC(C(N)=O)=C4NC3C=CC=C(OC)C=3)(=O)=O)C=CC=2)=O)C=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][CH2:80][CH2:81][C:82]1[CH:87]=[CH:86][C:85]([N:88]([CH3:123])[C:89]([C:91]2[CH:92]=[C:93]([S:97]([C:100]3[CH:101]=[C:102]4[C:107](=[C:108]([CH3:110])[CH:109]=3)[N:106]=[CH:105][C:104]([C:111]([NH2:113])=[O:112])=[C:103]4[NH:114][C:115]3[CH:120]=[CH:119][CH:118]=[C:117]([O:121][CH3:122])[CH:116]=3)(=[O:99])=[O:98])[CH:94]=[CH:95][CH:96]=2)=[O:90])=[CH:84][CH:83]=1>>[OH:68][C:65]1[CH:66]=[CH:67][C:58]([C@H:9]([CH2:10][NH:11][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][CH2:80][CH2:81][C:82]2[CH:87]=[CH:86][C:85]([N:88]([CH3:123])[C:89]([C:91]3[CH:92]=[C:93]([S:97]([C:100]4[CH:101]=[C:102]5[C:107](=[C:108]([CH3:110])[CH:109]=4)[N:106]=[CH:105][C:104]([C:111]([NH2:113])=[O:112])=[C:103]5[NH:114][C:115]4[CH:120]=[CH:119][CH:118]=[C:117]([O:121][CH3:122])[CH:116]=4)(=[O:99])=[O:98])[CH:94]=[CH:95][CH:96]=3)=[O:90])=[CH:84][CH:83]=2)[O:8][Si:1]([CH3:2])([CH3:3])[C:4]([CH3:5])([CH3:6])[CH3:7])=[C:59]2[C:64]=1[NH:63][C:62](=[O:69])[CH:61]=[CH:60]2
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)c5)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)c5ccc(CCCCOCCCCCCBr)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)c5ccc(CCCCOCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c6ccc(O)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 157, using Intermediate 99 in place of Intermediate 98. ES/MS calcd. for C54H73BrN6O9SSi+ 1069.5. Found m/z=1069.7 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1>CS(C)=O>[C:1]([CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1)#[N:2]
Reactant: BrCc1ccc(Oc2ccccc2)c2ccccc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc(Oc2ccccc2)c2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Sodium cyanide (3.7 g; 75 mMol) was dissolved in DMSO (50 mL, dried over molecular sieves). The mixture was heated in an oil bath maintained at 50° C., and 15.7 g (50 mMol) of 1-bromomethyl-4-phenoxynaphthalene, prepared as described above, in 75 mL of DMSO was added dropwise. After addition was complete, stirring was continued for 0.5 hours. The temperature was raised to 70° C., and stirring was continued for 1.0 hour. The oil bath was turned off, and the stirring was continued overnight. The mixture was poured onto ice, and extracted with ether. The combined organic extractions were washed with brine and dried over magnesium sulfate. The product was obtained as a white, crystalline solid (6.24 g; 49% yield). mass 259. A sample was purified for analysis by medium pressure chromatography on silica gel, eluting with ethyl acetate:hexane/1:9.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:17])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CN(Cc1ccccc1)C2
Reaction time: 32 h
Yield: 81.6 %

Procedure:
4.0 g of 2-benzyl-5-nitroisoindoline prepared in Reference Example 2-(2) was dissolved in 40 ml of methanol and 800 mg of 10% palladium on carbon was added to the solution. The catalytic hydrogenation was performed for 32 hours at room temperature and under atmospheric pressure. After removing the catalyst by filtration, the filtrate was concentrated to obtain 2.88 g of 2-benzyl-5-aminoisoindoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.C(O)C.[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:12]([O-:15])(=[O:14])=[O:13])[N:3]=1.[Na+:16]
Reactant: O=S([O-])[O-]
Reactant: Clc1cccc(Cl)n1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1cccc(Cl)n1
Temperature: 170 °C
Yield: 29.1 %

Procedure:
Into a 50 ml autoclave, 2.22 g (15 mmol) of 2,6-dichloropyridine and 4.5 ml of ethanol were introduced and dissolved. To the solution, 2.27 g (18 mmol) of sodium sulfite dissolved in 18 ml of water, was added, and after sealing, the mixture was heated in an oil bath of 170° C. for 12 hours. After completion of the reaction, the mixture was cooled, and after an addition of 30 ml of water, extracted with methylene chloride (30 ml×3 times). The aqueous layer was distilled under reduced pressure, and 200 ml of ethanol was added. The mixture was heated. After filtering off insoluble precipitates, the filtrate was distilled under reduced pressure to obtain 0.94 g (30%) of sodium 2-chloropyridine-6-sulfonate as crystalline solid. Purification was conducted by recrystallization from ethanol. The physical property values are shown below.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[NH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1>C1COCC1>[NH2:9][C:10]1[N:15]=[C:14]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH:13]=[C:12]([C:17]([F:20])([F:18])[F:19])[N:11]=1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(OCC(F)(F)F)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
2,2,2-Trifluoroethanol (2.2 mL, 30 mmol) was slowly added to a suspension of NaH (1.5 g, 36 mmol, 60% dispersion in mineral oil) in anhydrous THF (50 mL) under an N2 atmosphere. To the resulting mixture was added a solution of 2-amino-4-chloro-6-trifluoromethylpyrimidine (5.0 g, 25 mmol; for preparation see: Giner-Sorolla, A. and Bendich, A. J. Am. Chem. Soc. 1957, 80, 5744 and Gershon, H. et al. J. Het. Chem. 1983, 20, 219) in anhydrous THF (50 mL). The resulting mixture was stirred 18 h at room temperature and the solvent evaporated. The resulting residue was partitioned between CH2Cl2 (200 mL) and H2O (200 mL). The organics separated, dried over MgSO4, filtered and evaporated to afford 2-amino-4-(2,2,2-trifluoroethoxy)-6-trifluoromethyl-pyrimidine as a tan solid (4.9 g, 74% yield): m.p. 108-110° C.; 1H NMR (CDCl3) δ 6.54 (s, 1H), 5.53 (bs, 2H), 4.76 (q, 2H, J=8.2 Hz); GCMS (EI, 70 eV) m/z 261 (M+).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([OH:24])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26]([C:28]1[O:29][CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)=[O:27]>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([OH:24])[C:14]([C:32]3[CH:31]=[CH:30][O:29][C:28]=3[CH:26]=[O:27])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Reactant: CC1(C)OB(c2ccoc2C=O)OC1(C)C
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C=O)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 26, starting from tert-butyl 6-(benzenesulfonylmethyl)-3-bromo-2-hydroxybenzoate (Intermediate 38) and 2-formylfuran-3-boronic acid pinacol ester
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH2:17](Br)[CH:18]=[CH2:19]>>[CH2:19]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)[CH2:12][CH2:13]1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Product: C=CCN1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)piperidine and allylbromide, the titled compound was recovered by the procedure described in Example 1. MS m/z (relative intensity, 70 eV) 279 (M+, 74), 96 (bp), 82 (98), 68 (74), 55 (93). Rf=0.42 (MeOH, 0.08 (EtOAc).