Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5]([O:11][CH3:12])=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH3:28]>ClCl>[NH2:28][CH2:2][CH2:3][C:4]1[C:5]([O:11][CH3:12])=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1
Reactant: COc1nc(Cl)ccc1CCO
Reactant: N
Agent: ClCl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: COc1nc(Cl)ccc1CCN
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.20 g (0.8 mmol) of 3-(2-hydroxyethyl)-6-chloro-2-methoxypyridine in 10 ml of dry CH2 Cl2 cooled to -50° C. was added 0.18 ml (0.8 mmol) trifluoromethanesulfonic anhydride under an atmosphere of nitrogen. The mixture was stirred for 30 min at this temperature and an additional 10 min at -78° C. before a rapid addition of 30 ml of cold (-78° C.) NH3 (1). The mixture was stirred for 15 min at room temperature, and then concentrated in vacuo to afford 1.0 g of crude 3-(2-aminoethyl)-6-chloro-2-methoxypyridine as a trifluoromethanesulfonic acid salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+].O>C(OCC)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:10][CH3:9])=[N:3][CH:4]=1
Reactant: C[S-]
Reactant: Brc1ccc(Br)nc1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ccc(Br)cn1
Temperature: 160 °C
Yield: 89 %

Procedure:
2,5-Dibromo-pyridine (3.0 g, 12.7 mmol) and sodium thiomethoxide (0.84 g, 12 mmol) were dissolved in 18 ml anhydrous N N-dimethylformamide. The mixture was heated at 160° C. under nitrogen for 6 hrs. After cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The aqueous layer was extracted with ethyl acetate several times. The combined extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0→6% EtOAC/Hexane) to give 5-Bromo-2-methylsulfanyl-pyridine as a white solid (2.18 g, 84% yield). 1H-NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 7.09 (dd, 1H, J=0.7, J=8.6), 7.59 (dd, 1H, J=2.4, J=8.6), 8.50 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:10][CH3:9])=[N:3][CH:4]=1
Reactant: C[S-]
Reactant: Brc1ccc(Br)nc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(Br)cn1
Temperature: 160 °C
Yield: 89 %

Procedure:
2,5-Dibromo-pyridine (3.0 g, 12.7 mmol) and sodium thiomethoxide (0.84 g, 12 mmol) were dissolved in 18 ml anhydrous N,N-dimethylformamide. The mixture was heated at 160° C. under nitrogen for 6 hrs. After cooling to ambient temperature, water and ethyl acetate were added to the reaction mixture. The aqueous layer was extracted with ethyl acetate several times. The combined extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0→6% EtOAC/Hexane) to give 5-bromo-2-methylsulfanyl-pyridine as a white solid (2.18 g, 84% yield). 1H-NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 7.09 (dd, 1H, J=0.7, J=8.6), 7.59 (dd, 1H, J=2.4, J=8.6), 8.50 (m, 1H).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:8]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=2)[NH2:23])=[C:13]([CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32])[C:12]=1[O:35][CH3:36])(=[O:10])[CH3:9].N(CCO)(CCO)CCO>C(Cl)Cl>[C:8]([C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([NH:23][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[CH:24]=[CH:25][CH:26]=2)=[C:13]([CH2:29][CH2:30][C:31]([F:33])([F:32])[F:34])[C:12]=1[O:35][CH3:36])(=[O:10])[CH3:9]
Reactant: COC(=O)C(=O)Cl
Reactant: COc1c(C(C)=O)ccc(OCCCOc2cccc(N)c2)c1CCC(F)(F)F
Solvent: ClCCl
Solvent: OCCN(CCO)CCO
Product: COC(=O)C(=O)Nc1cccc(OCCCOc2ccc(C(C)=O)c(OC)c2CCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3.45 ml of methyl chlorooxalate in 10 ml of methylene chloride is added dropwise to a solution of 9.2 g of 3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-aniline and 4.3 ml of triethanolamine in 90 ml of methylene chloride in the course of 10 minutes. After stirring at room temperature for 5 hours, the mixture is poured onto water and extracted with methylene chloride. Evaporation of the extracts and recrystallisation of the residue from ether gives methyl N-{{3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-phenyl}}-oxamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([Si:14](Cl)([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:14]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Temperature: 0 °C
Yield: 95.7 %

Procedure:
5-Bromoindole (2.5 g, 12.75 mmol) was dissolved in tetrahydrofuran (THF; 50 mL) and cooled to 0° C. and Sodium Hydride NaH (920 mg, 23 mmol, 60%) was added in portions. The mixture was allowed to warm to RT with stirring for I hour. The reaction mixture was again cooled to 0° C. and triisopropylsilyl chloride (TIPSCl; 2.78 mL, 13.1 mmol) was added dropwise. The mixture was allowed to warm to room temperature and was stirred overnight. The mixture was washed with 2.0 N H3PO4, and the organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by flash silica chromatography (100% Hexanes) to give compound 8 as an oil (4.3 g; 96% yield; M+1=353.4)
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:5])[CH3:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CCOC(C)=O>[Br:1][CH2:2][CH:3]([CH3:4])[O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1
Reactant: C1=COCCC1
Reactant: CC(O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(CBr)OC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-bromopropan-2-ol (1.25 g, 9.0 mmol) and 3,4-dihydro-2H-pyran (2.04 ml, 22.5 mmol) in dichloromethane (50 ml) at 0° C. was added p-toluenesulfonic acid monohydrate (85 mg, 0.45 mmol). The reaction mixture was stirred at 0° C. for 15 min then warmed to room temperature and stirred for 2 h. The reaction was diluted with EtOAc and washed with water, sat NaHCO3, and brine then dried over MgSO4 and concentrated to afford 2-(2-bromo-1-methyl-ethoxy)-tetrahydro-2H-pyran as a light brown oil which was used without further purification.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][C:3](=O)[CH2:2]2.O1CCOCC1>O>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCC(CC2)N1
Solvent: C1COCCO1
Solvent: O
Product: C1CN2CCC(CC2)N1
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To the solution of 1,4-diazabicyclo[3.2.2]nonan-3-one (15.8 g; 113 mmol) in absolute dioxane (130 ml) LiAlH4 (4.9 g; 130 mmol) was added under argon. The mixture was refluxed for 6 hours and then allowed to reach room temperature. To the reaction mixture water (5 ml in 10 ml of dioxane) was added by drops, the mixture was stirred for 0.5 hour and then filtered off via glass filter. The solvent was evaporated and the residue was distilled using Kugelrohr apparatus at 90° C. (0.1 mbar) to yield 1,4-diazabicyclo[3.2.2]nonane (11.1 g; 78%) as colourless hygroscopic material.
Reaction SMILES: NC(N)=S.[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1)[CH3:6].[Br:17]Br>>[Br:17][CH2:15][C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH2:5][CH3:6])[CH:9]=1)=[O:16]
Reactant: BrBr
Reactant: CCOc1cccc(C(C)=O)c1
Agent: NC(N)=S
Product: CCOc1cccc(C(=O)CBr)c1

Procedure:
This compound was prepared from resin-bound thiourea of Example 24 and 2-bromo-(3-ethoxyphehyl)-ethanone by the procedure used in Example 36. MS (ES) MH+=453. The 2-bromo-(3-ethoxyphenyl)-ethanone was prepared by treating 1-(3-ethoxy-phenyl)-ethanone (prepared in accordance with the procedure in J. Chem. Soc. Perkin Trans. 2:1996, 755-760) with bromine as in Example 20C.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20]>O1CCCC1>[N+:29]([C:26]1[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:19](=[O:20])[O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)=[CH:28][CH:27]=1)([O-:31])=[O:30]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To an ice cooled solution, under argon, of 7.3 g of p-nitrophenol and 7.5 ml of triethylamine in 36 ml of dry tetrahydrofuran, is added, dropwise, a solution of 10.78 g of p-nitrobenzyl chloroformate in 18 ml of dry tetraydrofuran. The reaction mixture, a suspension, is stirred at room temperature overnight. The formed solid is collected, washed with water and dried to give 5.9 g of the desired product.
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[NH4+].[SH:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21].ClC(Cl)(Cl)C(O)=O.CCOCC>CN(C)C=O>[NH4+:6].[Cl:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][Cl:15])[P:4]1(=[O:5])[NH:6][CH:7]([S:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21])[CH2:1][CH2:2][O:3]1
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Reactant: O=S(=O)([O-])CCS
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=P1(N(CCCl)CCCl)NC(SCCS(=O)(=O)[O-])CCO1
Reaction time: 20 h

Procedure:
2.8 g (10 mmol) of 4-hydroxycyclophosphamide and 1.6 g (10 mmol) of ammonium-2-mercaptoethanesulphonate were dissolved with a catalytic quantity of trichloroacetic acid in 10 ml of dimethylformamide and were stored in a refrigerator at -25° C. for 20 hours. After a further 5 hours at 0° C., the mixture was mixed with ether until clouding commenced and was triturated. The crystallised material was filtered with suction after 1 day at 0° C., washed dried and recrystallised from n-propanol.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([O-:11])=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=C[CH:23]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.[Cl-]>[N+:1]([C:4]1[C:5]([C:9]([O:11][CH3:23])=[O:10])=[N:6][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: c1ccncc1
Reactant: O=C([O-])c1n[nH]cc1[N+](=O)[O-]
Reactant: OB(O)Oc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Product: COC(=O)c1nn(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
To a solution of 4-nitro-1H-pyrazole-3-carboxylate (1.0 g, 5.84 mmol) inmethylene chloride (20 mL) were added phenylboric acid (1.43 g, 11.7 mmol), copper(II) acetate (1.60 g, 8.76 mmol) and pyridine (2 mL, 23.4 mmol), and the mixture was stirred overnight at room temperature under an air atmosphere. After removal of the insolubles by filtration, the filtrate was washed with water (twice) and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain the title compound (1.21 g, 83.5%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].[Cl-:21].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:14][CH2:15][CH2:16][CH2:17][C:18]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][C:2]([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][Cl:21])=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1)=[O:19]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [Cl-]
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(CCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCl)ccc1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 23.6 g (0.142 mole) of fluorene and 50.0 g (0.35 mole) of 4-chlorobutyryl chloride in 1500 ml of methylene chloride chilled to -20° C. is added 39.8 g (0.298 mole) of aluminum chloride with rapid stirring. The reaction mixture is refluxed four hours, stirred at room temperature for 16 hours, then poured onto ice/conc. HCl. The organic layer is separated, washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. After filtration, the methylene chloride solution is evaporated to dryness and the solid residue recrystallized from acetone to yield 2,7-bis(4-chlorobutyryl)fluorene, M.P. 172°-175° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 120 °C
Yield: 95 %

Procedure:
To a solution of 4-(trifluoromethyl)phenol (3 g, 18.51 mmol) and 4-fluorobenzaldehyde (2.3 g, 18.53 mmol) in DMF (20 mL), was added Cs2CO3 (7.24 g, 22.21 mmol). The mixture was heated with a microwave condition at 120° C. for 4 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4 and evaporated in vacuo to afford the title compound (4.68 g, 95% yield) as a brown oil. LCMS: rt=3.58 min, [M+H+]=267
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C=O)C.O1CCOCC1.[Br:23][CH2:24][C:25](Br)=[O:26]>O>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:25](=[O:26])[CH2:24][Br:23])[CH:10]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 54 %

Procedure:
A solution of 2-amino-4-chlorobenzoic acid (10 g, 0.06 mmol), anhydrous DMF (30 mL) and anhydrous dioxane was cooled to 0° C. in 300 mL 3-necked flask fitted with magnetic stirrer and constant additional funnel. Bromoacetyl bromide was added dropwise over a 2 h period, keeping the internal temperature between 0°-2° C. After the addition was completed, the solution was allowed to warm to room temperature and the reaction mixture was stirred 20 h. The reaction mixture was cooled in an ice-bath and slowly diluted with water (300 mL). The resulting white crystalline product was filtered. Recrystallization from EtOAc/Hex afforded 9.2 g (54%) of the title compound, mp 156.4°-158° C.; 1H NMR (DMSO-d6) δ 13.99 (s, 1H, NH), 11.72 (s, 1H, COOH), 8.54 (d, 1H, J=2.0), 8.00 (d, 1H, J=8.8), 7.27 (dd, 1H, J=2.4, J=6.4), 4.28 (s, 2H); 13C NMR (DMSO-d6) δ 168.60, 165.54, 141.12, 138.51, 133.88, 123.36, 119.23, 115.58, 30.54; MS (EI, m/z) 293 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:37])[CH2:34][C:35]#[CH:36].CN(C=O)C>N(CC)CC.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>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][N:33]([CH3:37])[CH3:32])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCN(C)C
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CN(C)CC#Cc1cc(CN2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 1-dimethylamino-2-propyne (0.065 mL). Anhydrous DMF (10 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H20. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 1% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), 3% MeOH in CH2Cl2 (1L), 5% MeOH in CH2Cl2 (1L), and 6% MeOH in CH2Cl2 (1L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 153.5 mg (55%) of the desired product as a white solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH2:15][CH2:16][OH:17].C(Cl)(Cl)Cl>CO>[OH:17][CH2:16][CH2:15][NH:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: NCCO
Reactant: NC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(NCCO)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Add 6.0 g (0.03 moles) 4-chloro-3-nitrobenzamide to 60 ml 2-aminoethanol and stir at ambient temperature. When TLC (silica support; 9:1 CHCl3 :MeOH eluent) shows no starting material, ca. 3 hrs., pour onto ice. Filter, wash (3×15 ml) with cold H2O, and recrystallize from MeOH/IPA. Yield is 4.5 g (66%) of orange crystals.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.[Br:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17]Br)[CH:10]=1.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH2:17][C:1]#[N:2])[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1
Reactant: COc1cc(Br)cc(CBr)c1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(Br)cc(CC#N)c1
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 86.4 %

Procedure:
Sodium cyanide (3.4 g; WAKO) was added to a DMSO (100 mL) solution of Intermediate 2 (16.3 g) at room temperature and the resulting mixture was stirred at 40° C. for 1 hour and 40 minutes. Ethyl acetate (300 mL) and saturated aqueous sodium bicarbonate solution (150 mL), and water (150 mL) were added to extract the reaction mixture, the reaction mixture was washed with saturated brine (300 mL), the organic layer was dried, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen; n-hexane/ethyl acetate) to give the title compound (11.37 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[OH:11].[OH-].[Na+].CN1CCN(C)C1=O.Cl[CH:23]([F:25])[F:24]>O>[Br:1][C:2]1[C:3]([O:11][CH:23]([F:25])[F:24])=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)Cl
Reactant: O=[N+]([O-])c1cccc(Br)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: O=[N+]([O-])c1cccc(Br)c1OC(F)F
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 70.6 %

Procedure:
Into a 1-liter four-necked flask provided with a reflux condenser, a stirrer and a thermometer were fed 53.0 g (0.24 mol) of 2-bromo-6-nitrophenol, 40.5 g (0.49 mol) of 48% sodium hydroxide, 240 ml of 1,3-dimethylimidazolidine-2-one and 40.5 g of water. The mixture was heated to 80° C. and stirred at the same temperature for 1.5 hours with heating while chlorodifluoromethane (flon 22) was blown thereinto from a bomb. Then, while 20.0 g of 48% sodium hydroxide was added in seven portions, blowing of flon gas was continued at the same temperature for 7.5 hours. The total amount of flon gas blown was 242.3 g (2.80 mol). The reaction mixture was cooled. Thereto were added 26.0 g of 48% sodium hydroxide, 1 liter of water and 500 ml of ether, and extraction and layer separation was conducted. The organic layer was separated, and the water layer was subjected to reextraction using 500 ml of ether. The ether layers were combined and washed with 500 ml of water two times. The resulting organic layer was dried over anhydrous sodium sulfate and subjected to distillation to remove the solvent and obtain 45.4 g of 3-bromo-2-difluoromethoxynitrobenzene (yield: 70.6%, purity: 98.1%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]([C@@H:17]2[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C:4]2[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Fc1cc2nc(Cl)[nH]c2cc1F
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(F)c(F)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.943 g (5 mmole) of 12 in 25 mL of ClCH2CH2 Cl, was added 1.25 mL (5 mmole) of BSA at 75° C. The reaction mixture was stirred at 75° C. for 30 min. To this solution, was added 1.75 g (5.5 mmole) of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose and 1.07 mL (5.5 mmole) of TMSOTf. Stirring was continued at 75° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with 100 mL of CHCl3, and extracted with sat. NaHCO3 solution (100 mL×2) and sat. NaCl solution (100 mL). The CHCl3 phase was dried (Na2SO4) and evaporated. The residue was chromatographed on a silica column (3×25 cm, eluted successively with 0.5%, 1% MeOH/CHCl3). Evaporation of the appropriate fractions and recrystallization of the residue from MeOH gave 1.257 g (3 crops, 56%) of 64 as crystalline needles. MP 90°-91° C.; MS m/e 446.0694 (5%, M+ =446.0692); 1H NMR (DMSO-d6) d 7.93 (dd, 1, 7-H, 3JF-H =10.5 Hz, 4JF-H =7.5 Hz), 7.82 (dd, 1, 4-H, 3JF-H =10.5 Hz, 4JF-H =7.5 Hz), 6.23 (d, 1, 1'-H, J1'-2' =7.0 Hz), 5.55 (t, 1, 2'-H, J2'-3' =7.0 Hz), 5.44 (m, 1, 3'-H, J3-4 =4.5 Hz), 4.45 (m, 3, 4'-H and 5'-H), 2.13, 2.10, 2.02 (3×s, 9, 3×Ac); 13C NMR (DMSO-d6) d 169.95, 169.50, 169.18 (3×OCOCH3), 148.76, 148.62, 146.10, 145.93 (C5 and C6, 1JF-C =242 Hz), 140.16 (C2), 137.01 (C3a, 3JF-C =12 Hz), 128.54 (C7a, 3JF-C =12 Hz), 107.31, 107.09 (C4, JF-C =20 Hz), 100.93, 100.66 (C7, JF-C =24 Hz), 86.89 (Cl'), 79.41 (C4'), 70.40 (C2'), 68.62 (C3'), 62.67 (C5'), 20.43, 20.28, 20.00 (3×OCOCH3).