Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:11][NH:10][CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH:11]([C:31](=[O:32])[CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:10][CH2:9][CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: c1ccc(C23CCCC2CNCC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(Cc1ccccc1)C1NCCC2(c3ccccc3)CCCC12
Temperature: 25 °C

Procedure:
To a cold solution (0°-5° C.) of 3.0 g. of 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine in 47 ml. of methanol containing 14 ml. of water and 2.6 g. of potassium carbonate was added 2.6 g. of phenylacetyl chloride in one portion. The reaction mixture was stirred at 0°-5° C. for thirty minutes and then was warmed to 25° C., at which it was stirred for an additional one hour. The reaction mixture was concentrated under reduced pressure, leaving an oily residue. The oil was then dissolved in 500 ml. of diethyl ether and washed with dilute aqueous sodium bicarbonate solution and with water. After drying the ethereal solution, the solvent was evaporated under reduced pressure to afford 4a-phenyl-2-phenylacetyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine formed in the above acylation reaction as an oil.
Reaction SMILES: [CH2:1]([N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13]>>[CH2:1]([N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:14])[CH3:13])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1coc(Cn2cccc2)c1
Reactant: CC(=O)Cl
Product: CC(=O)c1cccn1Cc1ccco1

Procedure:
a. 1-furfuryl-2-acetyl-pyrrole was prepared starting from 1-furfuryl-pyrrole described by Reichstein in Helv. 15, 1450 (1932) as well as Gianturco et al. in Tetrahedron 207, 1763 (1964). Acetylation by reaction of the Grignard intermediate with acetyl chloride [cf. Chem. Ber. 47, 1416 (1914)] led to the desired ketone. (A small amount of the 3-isomer was also obtained, separable by fractional distillation). The product boils at 100°-102° C./0.03 mm Hg. and crystallizes on standing. Recrystallization from a mixture of methylene dichloride and petroleum ether gave a white crystalline product with a m.p. of 42°-43° C.
Reaction SMILES: [SH:1][CH2:2][CH:3]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][O:6][C:4]1=[O:5].[CH2:15]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18].N1C=CC=CC=1>C(OCC)C>[CH2:15]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([S:1][CH2:2][CH:3]2[CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7][O:6][C:4]2=[O:5])=[O:24])=[CH:26][CH:27]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: O=C1OCC(c2ccccc2)C1CS
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCc1ccc(C(=O)SCC2C(=O)OCC2c2ccccc2)cc1
Reaction time: 2.5 h
Yield: 79.1 %

Procedure:
To a solution of 1.5 g of α-mercaptomethyl-β-phenyl-γ-butyrolactone in 30 ml of ethyl ether were added at room temperature 4.3 g of p-n-butylbenzoyl chloride and then 1.9 ml of pyridine. The mixture was kept at room temperature for 2.5 hours. After completion of the reaction, the reaction mixture was diluted with 100 ml of ethyl ether, washed with 10% hydrochloric acid, 10% aqueous sodium hydrogen carbonate and then satureated saline, dried over magnesium sulfate and the solvent was distilled off. The crude product thus obtained was purified by a silica gel column chromatography to give 2.1 g (yield 79%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.N1C=CC=CC=1.[CH3:29][CH:30]1[CH2:35][NH:34][CH2:33][CH2:32][NH:31]1>C(O)C>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:34]4[CH2:33][CH2:32][NH:31][CH:30]([CH3:29])[CH2:35]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: CCO
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(C)C4)cc3nc21

Procedure:
1-Ethyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 1 but starting from 2.1 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid, 20 cm3 of pyridine and 2.4 g of 2-methylpiperazine. After taking up in ethanol and concentrating to dryness under reduced pressure (20 kPa at 50° C.), the solid residue is taken up in 20 cm3 of water and 10 cm3 of 2 N potassium hydroxide solution. The aqueous solution obtained is washed with twice 20 cm3 of trichloromethane, 10 cm3 of acetic acid are added and the mixture is again washed with twice 40 cm3 of trichloromethane. 23 cm3 of 4.5 N potassium hydroxide solution are added and the suspension obtained is heated to a temperature close to 90° C. After cooling to a temperature close to 20° C., the precipitate is drained and washed with 3 times 10 cm3 of water and twice 10 cm3 of ethanol. After recrystallizing twice from 120 cm3 of dimethylformamide each time, 1.7 g of 1-ethyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 310°-312° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][O:32][CH2:33][CH2:34]Br>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:34][CH2:33][O:32][CH3:31])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: CCOC(=O)c1cc(-c2cccc(O)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(-c2cccc(OCCOC)c2)n(-c2cccc(Cl)c2)n1

Procedure:
100 mg (0.292 mmol) of the compound of Example 44A are provided in 2 ml of dry acetone, 44.4 mg (0.321 mmol) of potassium carbonate and 40.6 mg (0.292 mmol) of 2-bromoethyl methyl ether are added, and the mixture is heated under reflux overnight. The reaction mixture is subsequently purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with the addition of 0.1% formic acid) and 48 mg (41% of theory) of the title compound are obtained.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>O>[CH3:34][O:33][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[N:18]=[CH:17][CH:16]=[C:15]2[O:21][C:22]1[C:23]([CH3:32])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCCl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCN1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 375) (40 mg), potassium carbonate (41 mg), and piperidine (25 mg), and the mixture was stirred at 75° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (32 mg, yield 72%).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[C:9](=[O:17])[N:8]([CH3:18])[CH2:7][C:6]=12.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:24][C:20]([CH3:21])([CH3:19])[C:22]#[C:23][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[C:9](=[O:17])[N:8]([CH3:18])[CH2:7][C:6]=12
Reactant: Cc1cccc2c1C(=O)N(C)Cc1c(I)ncn1-2
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: Cc1cccc2c1C(=O)N(C)Cc1c(C#CC(C)(C)O)ncn1-2

Procedure:
5 g (14.2 mmol) of 4,5-dihydro-3-iodo-5,7-dimethyl-6H -imidazo[1,5-a][1,4]benzodiazepin-6-one were heated to boiling under reflux for 4.5 hours with 1.50 g (17.8 mmol) of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenyl -phosphine)-palladium(II) dichloride and 20 mg of copper(I) iodide in 40 ml of diethylamine. The reaction mixture was then evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. By recrystallization from ethyl acetate there was obtained 4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5,7-dimethyl -6H-imidazo-[1,5-a][1,4]benzodiazepin-6-one of melting point 165-167°.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[S:37][CH:38]=[CH:39][N:40]=1)CCC>>[S:37]1[CH:38]=[CH:39][N:40]=[C:36]1[C:2]1[C:10]2[NH:9][C:8]([N:11]3[CH2:12][CH2:13][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:15][CH2:16]3)=[N:7][C:6]=2[CH:5]=[C:4]([C:27]([F:29])([F:30])[F:28])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Product: FC(F)(F)c1cc(-c2nccs2)c2[nH]c(N3CCN(c4ncccc4C(F)(F)F)CC3)nc2c1

Procedure:
The reaction of 4-bromo-6-trifluoromethyl-2-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1H-benzoimidazole (148 mg, 0.3 mmol, Example 7) with 2-tributylstannylthiazole (Matrix Scientific) under the conditions of Example 35 gave the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 499 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([C:21]([O:23]C)=[O:22])=[CH:20][C:7]1=2.CO.[OH-].[Na+].Cl>O>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:7]1=2
Reactant: COC(=O)c1ccc2c(c1)C(=CCCN(C)C)c1ccccc1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)CCC=C1c2ccccc2COc2ccc(C(=O)O)cc21
Yield: 99.9 %

Procedure:
In this example, 26.1 g of methyl 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate is dissolved in a mixed solvent of 500 ml of methanol and 30 ml of water and 6.2 g of sodium hydroxide is added thereto. The mixture is heated at reflux for two hours. After allowing the mixture to stand for cooling, aqueous 4N-hydrochloric acid solution is added thereto to adjust the pH to 7 and the mixture is concentrated under reduced pressure. The concentrate is purified by column chromatography on high porous polymer (HP-20) (eluent: water:methanol=1:2) to obtain 25.0 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[C:11]([CH3:12])=[N:10][O:9][N:8]=1)=[O:5].[CH2:25](Br)[CH:26]=[CH2:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:27]([N:6]([C:7]1[C:11]([CH3:12])=[N:10][O:9][N:8]=1)[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][C:15]([C:21]([F:24])([F:23])[F:22])=[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])[C:2]=1[CH3:1])[CH:26]=[CH2:25]
Reactant: Cc1nonc1NC(=O)c1ccc(C(F)(F)F)c(S(C)(=O)=O)c1C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(C(=O)c1ccc(C(F)(F)F)c(S(C)(=O)=O)c1C)c1nonc1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
150 mg (0.413 mmol) of 2-methyl-N-(4-methyl-1,2,5-oxadiazol-3-yl)-3-(methylsulfonyl)-4-(trifluoromethyl)benzamide and 50 mg (0.413 mmol) of allyl bromide are dissolved in 5 ml of N,N-dimethylformamide, and 0.057 mg (0.413 mmol) of potassium carbonate is added. The reaction mixture is stirred at 80° C. for 8 h and taken up in 5 ml of water and extracted twice with 10 ml each time of dichloromethane. The organic phase is dried over Na2SO4 and concentrated. The residue is purified by means of preparative HPLC (acetonitrile, water). Yield 160 mg (86%).
Reaction SMILES: [SiH](CC)(CC)CC.B(F)(F)F.CCOCC.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31](O)[C:32]([CH3:43])([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]([OH:35])=[O:34])=[CH:27][C:26]=1[O:45][CH3:46])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([CH3:43])([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:33]([OH:35])=[O:34])=[CH:27][C:26]=1[O:45][CH3:46])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc(C(O)C(C)(Oc2ccccc2)C(=O)O)ccc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCc1ccccc1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of Et3SiH (8.67 mL, 54.3 mmol) in CH2Cl2 (45 mL) was treated with BF3.Et2O (6.8 mL, 54.3 mmol). 3-(4-Benzyloxy-3-methoxyphenyl)-3-hydroxy-2-methyl-2-phenoxypropionic acid (7.39 g, 18.1 mmol) in CH2Cl2 (90.5 mL) was then added dropwise via addition funnel, maintaining temperature below −7° C. After the addition was complete, the reaction was stirred for 1.5 h at −10° C., then quenched with 1 M NaOH (18.1 mL) and diluted with H2O (12 mL). 1N HCl was used to adjust pH to 4, followed by separation of layers. The aqueous layer was extracted with CH2Cl2 (2×15 mL), and combined organic layers were washed first with 1N HCl (15 mL), then H2O (15 mL), followed by drying over Na2SO4 and concentration to a gummy orange solid (6.86 g, 97%): MS (EI) 410.2 (M+NH4)+, 391.3 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](Cl)=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[CH3:25][NH2:26]>O1CCCC1>[CH3:25][NH:26][C:15](=[O:16])[CH:14]([O:13][C:12]1[CH:19]=[CH:20][C:9]([O:8][C:7]2[CH:21]=[CH:22][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1)[CH3:18]
Reactant: CN
Reactant: CC(Oc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1)C(=O)Cl
Solvent: C1CCOC1
Product: CNC(=O)C(C)Oc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
Into a solution of 3.61 g. (0.01 mole) of 2-[[4-[4-(trifluoromethoxy)phenoxy]phenoxy]]propanoyl chloride in 20 ml. of tetrahydrofuran (THF) is passed a stream of gaseous methylamine. When the reaction is over, the solvent is removed and the residue treated with methylene chloride. The methylene chloride solution is washed with water, dried, and the solvent removed, providing a residue of 2-[[4-[4-(trifluoromethoxy)phenoxy]phenoxy]]propanoic acid, N-methyl amide.
Reaction SMILES: [F:1][CH2:2][C:3]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:7][CH2:6][N:5]([C@H:8]([C:13]2[CH:14]=[N:15][C:16]([NH:19][NH2:20])=[CH:17][CH:18]=2)[C:9]([F:12])([F:11])[F:10])[CH2:4]1.[CH3:29][O:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[C:38]([CH:41]=O)[CH:37]=[CH:36]2>>[F:1][CH2:2][C:3]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:7][CH2:6][N:5]([C@H:8]([C:13]2[CH:18]=[CH:17][C:16]3[N:15]([C:41]([C:38]4[CH:37]=[CH:36][C:35]5[C:40](=[C:31]([O:30][CH3:29])[CH:32]=[CH:33][CH:34]=5)[N:39]=4)=[N:20][N:19]=3)[CH:14]=2)[C:9]([F:12])([F:10])[F:11])[CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1(CF)CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COc1cccc2ccc(C=O)nc12
Product: COc1cccc2ccc(-c3nnc4ccc([C@@H](N5CCC(CF)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12

Procedure:
Prepared as described in Example 9B using tert-butyl 3-(fluoromethyl)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (Example 154; 0.20 g, 0.491 mmol) in place of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidine-3-ylcarbamate and 8-methoxyquinoline-2-carbaldehyde (0.092 g, 0.491 mmol) in Step E (0.229 g, 81%). LCMS APCI (+) m/z 575 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4](F)[CH:3]=1.[OH-:15].[Na+]>O>[F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([OH:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1O

Procedure:
0.41 g of 1,3-difluoro-4,6-dinitrobenzene was dissolved in 8 ml of 0.5 N aqueous sodium hydroxide solution and refluxed for 2 hours. After cooling, it was diluted with water and extracted three times with diethyl ether. The aqueous phase was made acidic by adding 1N hydrochloric acid and extracted with diethyl ether. The organic phase was dried on sodium sulfate and concentrated by evaporation in a vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[CH2:16][N:15]([C:30](Cl)=[O:31])[CH2:14]3)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:33]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34]1>>[NH2:38][CH:35]1[CH2:36][CH2:37][N:33]([C:30]([N:15]2[CH2:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:18][CH:13]([C:11]3[O:10][N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[N:12]=3)[CH2:14]2)=[O:31])[CH2:34]1
Reactant: O=C(Cl)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1
Reactant: NC1CCNC1
Product: NC1CCN(C(=O)N2CC(c3ccc(OC(F)(F)F)cc3)CC(c3nc(-c4cccc(F)c4)no3)C2)C1

Procedure:
100 mg (0.21 mmol) of the compound from Example 179A and 34 mg (0.21 mmol) of pyrrolidine-3-amine were reacted according to the General Method 5. Yield: 32 mg (28% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:17])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])([O-:3])=[O:2].[N+:18]([O-])([O-:20])=[O:19].[K+]>S(=O)(=O)(O)O>[N+:18]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:9]([O:10][CH:11]([F:16])[C:12]([F:14])([F:15])[F:13])[CH:8]=[CH:7][C:6]=1[CH3:17])([O-:20])=[O:19]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc(OC(F)C(F)(F)F)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1ccc(OC(F)C(F)(F)F)c([N+](=O)[O-])c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
1.5 g (5.9 mmoles) 3-nitro-4-tetrafluoroethoxytoluene is placed in 7.5 ml concentrated sulfuric acid and 0.65 g (6.4 mmoles) potassium nitrate in 3 ml concentrated sulfuric acid is added dropwise at 0° C. After the addition is terminated it is agitated for 2 hours at ice bath temperature and then poured onto ice. The dinitro compound precipitates as an oil and is extracted with ether. The combined ether phases are washed with sodium bicarbonate solution and water and dried over sodium sulfate. When the solvent is distilled the 2,3-dinitro-4-tetrafluoroethoxytoluene remains as a yellow oil which crystalizes after standing for a short time. Yield: 1.55 g (88% of the theoretical yield), melting point: 35° C.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[C:60]([O:64][C:65]([NH:67][C@H:68]([C:83](OCC#N)=[O:84])[CH2:69][CH2:70][C@@H:71]1[S:75][CH2:74][N:73]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])[CH2:72]1)=[O:66])([CH3:63])([CH3:62])[CH3:61]>C(#N)C>[NH2:58][C:55]1[CH:56]=[CH:57][N:52]([C@@H:26]2[O:25][C@H:24]([CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]3[C@@H:39]([O:40][C:83](=[O:84])[C@@H:68]([NH:67][C:65]([O:64][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:66])[CH2:69][CH2:70][C@@H:71]4[S:75][CH2:74][N:73]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])[CH2:72]4)[C@@H:38]([OH:41])[C@H:37]([N:42]4[CH:50]=[N:49][C:48]5[C:43]4=[N:44][CH:45]=[N:46][C:47]=5[NH2:51])[O:36]3)([OH:32])=[O:31])[CH2:27]2)[C:53](=[O:59])[N:54]=1
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC[C@H]1CN(C(=O)OC(C)(C)C)CS1)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC[C@H]1CN(C(=O)OC(C)(C)C)CS1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 25 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (44.0 mg, 0.069 mmol) and (S)-tert-butyl 5-((S)-3-((tert-butoxycarbonyl)amino)-4-(cyanomethoxy)-4-oxobutyl)thiazolidine-3-carboxylate (Compound tk3) (89 mg, 0.207 mmol) in acetonitrile (0.3 mL) was added to buffer A (12.5 mL), and the mixture was stirred at room temperature for 1.25 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (5S)-tert-butyl 5-((3S)-4-(((2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl)Oxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)thiazolidine-3-carboxylate (Compound tk4) (17.4 mg, 25%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH2:17]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2)[CH2:18][CH2:19][CH3:20]>>[CH2:17]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[C:24]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1)[CH2:18][CH2:19][CH3:20]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: CCCCc1ccc2c(c1)CC(=O)N2
Product: CCCCc1ccc2c(c1)C(=Cc1cc(C(C)C)c(OC)c(C(C)C)c1)C(=O)N2

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-butyl-2-oxindole to give 0.3 g of 5-butyl-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]#[C:14][CH3:15])=[CH:7][N:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1)[C:13]#[C:14][CH3:15]
Reactant: CC#CCOc1ccc(C(=O)OC)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC#CCOc1ccc(C(=O)O)nc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of 5-but-2-ynyloxy-pyridine-2-carboxylic acid methyl ester (234 mg) in THF (20 ml) and water (15 ml) was added aqueous LiOH (1M, 2.3 ml) and the mixture was stirred at 22° C. for 1 h. The mixture was treated with aqueous HCl (1M, 2.3 ml), evaporated slowly, the suspension obtained was filtered, the residue washed with water and dried to give the title product (165 mg) as a white solid. MS: m/z=192.1 [M+H]+.