Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C[O-].[Na+].[CH:10]1([CH2:13]Br)[CH2:12][CH2:11]1>CO>[CH:10]1([CH2:13][S:1][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: BrCC1CC1
Reactant: Sc1nc[nH]n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1nc(SCC2CC2)n[nH]1
Reaction time: 10 h
Yield: 99.1 %

Procedure:
To a solution of 3-mercapto-1,2,4-triazole (7.1 g) and sodium methoxide (3.8 g) in methanol (100 ml), there was added cyclopropylmethyl bromide (9.5 g), and the resultant mixture was allowed to stand at room temperature for 10 hours. After removal of the solvent, the residue was extracted with chloroform. Evaporation of the chloroform extract gave 10.8 g of 3-cyclopropylmethylthio-1,2,4-triazole. Yield, 99%. M.P., 69°-70° C.
Reaction SMILES: C1C=C2O[C@@H](CO)COC2=C(N2CCN(CCN[C:22]([C:24]3[CH:25]=[CH:26][C:27](F)=[CH:28][CH:29]=3)=[O:23])CC2)C=1.C(Cl)[Cl:32]>>[C:22]([Cl:32])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(NCCN1CCN(c2cccc3c2OC[C@H](CO)O3)CC1)c1ccc(F)cc1
Reactant: ClCCl
Product: O=C(Cl)c1ccccc1

Procedure:
Preparation of flesinoxan from R-(+)-BDA ##STR13## (a). Benzoylation of R-(+)-BDA(1) with benzoyl chloride in methylene chloride as the solvent, to produce compound (2).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][N:5]=1)([O-:3])=[O:2].S(Cl)([Cl:15])=O>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])nc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])nc1

Procedure:
To 6-nitronicotinic acid (3.5 g) is added thionyl chloride (50 ml), and the mixture is refluxed for three hours, and evaporated to remove thionyl chloride to give 6-nitronicotinoyl chloride, which is added with stirring to a solution of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-benzazepine (3.4 g) in pyridine (50 ml) under ice-cooling. The mixture is stirred at room temperature overnight. To the reaction mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed successively with 0.1N aqueous hydrochloric acid and water, and dried over magnesium sulfate. The resultant is evaporated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography to give 7-chloro-5-oxo-1-(6-nitronicotinoyl)-2,3,4,5-tetrahydro-1H-benzazepine (4.9 g) as colorless amorphous.
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[CH:26]=[CH:25][C:16]2[N:17]([CH3:24])[C:18](=[O:23])[CH2:19][S:20](=[O:22])(=[O:21])[C:15]=2[CH:14]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1.Cl>CN(C)C=O>[Cl:12][C:13]1[CH:26]=[CH:25][C:16]2[N:17]([CH3:24])[C:18](=[O:23])[CH:19]([C:35](=[O:36])[NH:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)[S:20](=[O:22])(=[O:21])[C:15]=2[CH:14]=1
Reactant: CN1C(=O)CS(=O)(=O)c2cc(Cl)ccc21
Reactant: O=C=Nc1ccc(F)cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CN1C(=O)C(C(=O)Nc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 1,8-diazabicyclo-[5,4,0]undec-7-ene (14.12 g) in dimethylformamide (111 ml) was added, dropwise in 10 minutes, a solution of 7-chloro-4-methyl-2H-1,4-benzothiazin-3(4H)one 1,1-dioxide (22.8 g) and 4-fluorophenylisocyanate (12.82 g) in dimethylformamide (111.4 ml) at room temperature. After being stirred for one hour, the mixture was poured into 1% hydrochloric acid (1 l). The separated solids were collected by filtration and washed with water. The wet solids were dissolved in ethyl acetate. The mixture was washed with 1% hydrochloric acid, with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from diethyl ether to yield 24.3 g of 7-chloro-2-(4-fluorophenylcarbamoyl)-4-methyl-2H-1,4-benzothiazin-3(4H)one 1,1-dioxide.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([NH2:27])[CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([NH:27][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:26]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
4-Nitrobenzaldehyde (0.302 g, 2.0 mmol) was added to a stirred mixture of 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.476 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 4 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture was stirred for 2 hours. The mixture was shaken, the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give an orange solid. Recrystallization from ethyl acetate gave the product (290 mg), mp 198-199° C.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10](=S)[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].[N:31]([Si](C)(C)C)=[N+:32]=[N-:33].C(OCC)(=O)C>ClCCl.[Fe](Cl)(Cl)Cl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:33]=[N:32][N:31]=2)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=S)NCc3ccncc3)c(=O)c1Br)C2(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: Cl[Fe](Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(Cc3nnnn3Cc3ccncc3)c(=O)c1Br)C2(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.4 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)ethanethioamide (38 mg, 0.077 mmol) in dichloromethane (1 mL) was mixed with azidotrimethylsilane (41 μL, 0.308 mmol) and iron trichloride (30 mg, 0.185 mmol) at room temperature and stirred at room temperature for 17 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=50/1) to give the desired product (9 mg, 24% yield).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH2:20]O)[C:6]2[N:10]=[N:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:7]=2[CH:19]=1.C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:25][CH2:20][C:5]1[C:6]2[N:10]=[N:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:7]=2[CH:19]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[Si](C)(C)CCOCn1nnc2c(CO)cc(C(F)(F)F)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nnc2c(CBr)cc(C(F)(F)F)cc21
Reaction time: 0.5 h

Procedure:
To a solution of (6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)methanol (165 mg, 0.475 mmol) and carbon tetrabromide (236 mg, 0.712 mmol) in tetrahydrofuran (2 mL) at 0° C. was added triphenylphosphine (187 mg, 0.712 mmol). The ice bath was removed and stirring continued at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids which were discarded. The organics were concentrated and purified by column chromatography (4→8% ethyl acetate/hexanes) to give 159 mg (82%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.96 (s, 1H), 7.67 (s, 1H), 6.03 (s, 2H), 5.04 (s, 2H), 3.59 (m, 2H), 0.90 (m, 2H), −0.07 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 145.9, 132.6, 131.6, 130.4 (q, J=33 Hz), 123.7 (q, J=273 Hz), 121.6 (q, J=2.9 Hz), 108.6 (q, J=4.8 Hz), 67.7, 25.9, 17.7, −1.5.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[Cl:52][C:53]1[CH:54]=[CH:55][C:56]2[NH:65][CH2:64][C:63]3[CH:62]=[N:61][N:60]([CH3:66])[C:59]=3[NH:58][C:57]=2[CH:67]=1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([C:16]([N:65]2[CH2:64][C:63]3[CH:62]=[N:61][N:60]([CH3:66])[C:59]=3[NH:58][C:57]3[CH:67]=[C:53]([Cl:52])[CH:54]=[CH:55][C:56]2=3)=[O:18])[CH2:14][CH2:15]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1NC2
Reactant: CC(C)(C)OC(=O)NCC1CCC(C(=O)O)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)C1CCC(CNC(=O)OC(C)(C)C)CC1)C2
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid from Example E9 (510 mg, 2.0 mmol) in dichloromethane (25 ml) at room temperature was treated with DIEA (0.70 ml, 4.0 mmol), PyBrop (2.40 g, 5.1 mmol), and 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E1 (422 mg, 1.8 mmol) and the resulting solution was heated at reflux for 20 h and allowed to cool to room temperature. The solution was diluted with dichloromethane, washed with brine and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant EtOAc) to yield the title compound (775 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]([OH:23])(=O)[CH3:21]>O>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:20](=[O:23])[C:21]3[CH2:2][CH2:3][CH2:4][CH2:5][C:7]=3[C:8]2=[O:9])=[C:4]([F:19])[CH:3]=1
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Reactant: CC(=O)O
Solvent: O
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 175.4 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetarhydrophthalic anhydride (7.56 g) and acetic acid (50 g) was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature, and water (75 g) was added thereto. The precipitated crystals were collected by filtration to give the compound (I) (15.4 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH:13](O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH:13]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:23][C:24]=2[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Yield: 94.5 %

Procedure:
Substantially the same procedure as in Reference Example 4 was repeated using 4-benzyloxybenzhydrol (30.0 g, 103 mmol) and ethyl indole-2-carboxylate (18.5 g, 97.9 mmol) to give 42.7 g (yield: 95%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[CH2:20]([Si:22](Cl)([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].CCOCC>C1COCC1>[F:1][C:2]1[C:3]([NH:17][Si:22]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:20][CH3:21])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[Si](CC)(CC)Nc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a magnetically stirred mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.25 g, 1.05 mmol) in dry THF (5 mL) at 0° C. was added NaH (0.042 g of 60 wt. % suspension in mineral oil, 1.05 mmol). When bubbling ceased, triethylsilyl chloride (0.158 g, 1.05 mmol) was added dropwise (neat) via syringe. After stirring overnight at ambient temperature, the reaction mixture was poured into ether and washed with a mixture of aqueous saturated sodium bicarbonate and brine solution. The organic layer was separated, dried over Na2SO4, filtered, and evaporated to give a white solid. This crude material was purified on silica by column chromatography (EtOAc/hexanes gradient) to give 0.121 g (33%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]-triethylsilanylamine as a clear yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=2.5 Hz, 1H), 7.39 (m, 2H), 7.03 (t, J=8.6 Hz, 2H), 5.27 (s, 2H), 4.53 (s, 1H), 0.99 (m, 9H), 0.83 (m, 6H); HPLC-MS (ESI) m/z 352 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=O)[CH2:11][C:12](=[O:30])[C:13](=[N:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:14](=[O:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>C(#N)C>[C:14]([C:13]1[C:12](=[O:30])[CH:11]=[C:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:17]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)C(=NNc1ccccc1OC(C)(C)C)C(=O)CC(=O)COCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)c1nn(-c2ccccc2OC(C)(C)C)c(COCc2ccccc2)cc1=O
Yield: 65.9 %

Procedure:
A solution of 1-(benzyloxy)-5-[(2-tert-butoxyphenyl)hydrazono]heptane-2,4,6-trione (5.58 g) and triethylamine (9.61 g) in acetonitrile (55 mL) was heated under reflux for 1 hr. After cooling, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.52 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[H-].[Na+].CN(C=O)C.Cl.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[N:20][N:19]=1>O>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([O:1][CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:19][N:20]=2)=[CH:34][CH:33]=1
Reactant: Clc1ccc(Nc2nnc(Cl)c3ccccc23)cc1
Reactant: OCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(Nc2nnc(OCc3ccncc3)c3ccccc23)cc1
Reaction time: 0.33 h

Procedure:
A mixture of 1 g (9.16 mmol) 4-hydroxymethylpyridine, 0.44 g (11.0 mmol) sodium hydride (60% dispersion in oil) and 15 ml DMF is incubated for 20 min at 0° C. while stirring in a nitrogen atmosphere. At RT, 1 g (3.07 mmol) 1-chloro-4-(4-chloroanilino)phthalazine hydrochloride is added to the mixture, which is stirred for about 1 h at 500C and for 15 h at 80° C. Addition to the reaction mixture of a little water, evaporation under vacuum, recrystallization of the residue from methanol, and drying under HV yield the title compound with a water content of 3.36%; m.p. 139-141° C.; ESI-MS: (M+H)+=363.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:38]([O:42][C:43](Cl)=[O:44])[CH:39]([CH3:41])[CH3:40].CCOCC>ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([O:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([O:21][C:43](=[O:44])[O:42][CH2:38][CH:39]([CH3:41])[CH3:40])[CH:15]=[CH:14]3)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)COC(=O)Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
Dissolve the compound of Example 3 (120 mg, 0.23 mmol) in dichloromethane (3 mL) and add isobutylchloroformate (38 μL, 0.30 mmol) dropwise. After stirring for 10 minutes, pour the reaction into vigorously stirred ether (10 mL) and filter. Dissolve the solids in dichloromethane (10 mL) and wash with saturated aqueous sodium bicarbonate. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol in dichloromethane (4%) to give 104 mg of the title compound (73%): mass spectrum (ion spray): m/z=618.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:43]=[O:44].Cl>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([CH:43]=[O:44])=[CH:7][C:6]=3[C:5]2([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:14]=1
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 2,7-dibromo-9,9-didecylfluorene (95.5 g, 0.158 mol) in terahydrofuran (THF, 375 mL), cooled In a dry-ice acetone bath, a 1.6 M solution of n-butyl lithium in hexanes (100 mL) was added over a period of 25 minutes. After stirring for 30 minutes a solution of dimethylforamide (DMF, 23 mL) in THF (25 ml) was added and the mixture was stirred for 1 hour in the cooling bath. After the mixture had been warmed to 0° C., hydrochloric acid (1:1, 50 mL) was added, diluted with toluene and the organic phase was separated, dried and concentrated. The residue that remained after rotary evaporation of the solvents was chromatographed over 600 g of silica gel. After elution with hexanes, the column was eluted with 1:3 toluene-hexane to obtain the aldehyde, 70.5 g, (81% yield), m.p. 45-47° C. A sample was recrystallized from a mixture of isopropanol and methanol, m.p. 49-49.5° C. IR (KBr; cm−1): 2922, 2853, 1696 (C═O), 1605, 1459. Anal. Calcd. for C34H49BrO: C, 73.76%; H, 8.92%; Br, 14.43%. Found: C, 73.75%; H, 8.86%; Br, 14.64%.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]4([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[OH:28])[CH2:21][CH2:20]4)[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:36][CH2:35][CH2:34][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1([NH:18][C:14]2[C:13](=[O:29])[N:12]([C:10]3[CH:11]=[C:6]([CH:7]=[C:8]([F:31])[C:9]=3[CH3:30])[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:32])[CH:17]=[CH:16][N:15]=2)[CH2:21][CH2:20]1
Reactant: ClCCBr
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O

Procedure:
N-Cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (Example 259c 5 g), 1-bromo-2-chloroethane (9.58 mL) and cesium carbonate (37.5 g) were stirred together in acetonitrile (200 mL) at 80° C. under nitrogen for 16 h. The cooled reaction mixture was evaporated to dryness, diluted with water (500 mL) and extracted with dichloromethane (3×300 mL). The combined organics were dried (MgSO4), filtered and evaporated. The residue was triturated with 1:1 iso-hexane:diethyl ether to give the subtitle compound (4.60 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH2:14](O)CCCCCCCCCCC>[Ni]>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH3:14])=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccnc2)cc1
Reactant: CCCCCCCCCCCCO
Agent: [Ni]
Solvent: O
Product: Cc1ccc(-c2ccccc2)cn1
Temperature: 25 °C

Procedure:
A suspension of 100 g of wet Raney Nickel in 1.5 L of dodecanol in a three-neck round bottom flask equipped with a Dean Stark apparatus was heated until the temperature reached 130° C., then 3-phenylpyridine (Aldrich) was added and the reaction was heated at 190°-200° C. for 6 hours. During the reaction, H2O was constantly eliminated. When the reaction was over, half of the dodecanol was removed by distillation. After cooling the reaction mixture to room temperature, 200 mL of H2O and 400 mL of hexane were added, the mixture was shaken, and the hexane layer decanted. This process was repeated several times. The combined hexane fractions were washed with 1N HCl until the disappearance of 5-phenyl-2-picoline from the organic phase. The combined aqueous layers were filtered, washed with hexane, basified with 10N NaOH, and extracted with CH2Cl2. The organic layer was washed with NH4OAc (25%), dried over MgSO4, and evaporated to dryness. The crude residue was then distilled under vacuum (100° C. at 0.1 mm of Hg) to afford the pure title product.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C@H:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:49]1[CH:50]=[C:51]([P:55]([CH3:60])(=[O:59])[O:56][CH2:57][CH3:58])[CH:52]=[CH:53][CH:54]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:47][C@H:48]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:49]2[CH:50]=[C:51]([P:55]([CH3:60])(=[O:59])[O:56][CH2:57][CH3:58])[CH:52]=[CH:53][CH:54]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Reactant: CCOP(C)(=O)c1cccc([C@H](N)c2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1cccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (7.9 g, 25.7 mmol) and Et3N (7.09 g, 70.2 mmol) in MeCN (50 ml) was added HATU (10.7 g, 28.2 mmol). The mixture was stirred for 10 min at room temperature and then ethyl 3-((R)-amino(phenyl)methyl)phenyl(methyl)phosphinate, 24-e, (6.79 g, 23.4 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with saturated NH4Cl. The organic layer was dried over sodium sulfate and concentrated under vacuum to provide the crude product, 24-f, (18.8 g) as red oil. The crude product was used for the next step directly.