Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:67]1([CH2:72][C:73]2[CH:80]=[CH:79][C:76]([CH:77]=O)=[CH:75][CH:74]=2)[CH:71]=[CH:70][CH:69]=[N:68]1>C(O)C.CN(C=O)C>[N:67]1([CH2:72][C:73]2[CH:80]=[CH:79][C:76]([C:77]3[NH:42][C:39]4=[N:40][CH:41]=[C:36]([Br:35])[C:37]([N:46]5[CH2:51][CH2:50][N:49]([CH2:52][C:53]6[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=6)[CH2:48][CH2:47]5)=[C:38]4[N:43]=3)=[CH:75][CH:74]=2)[CH:71]=[CH:70][CH:69]=[N:68]1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(Cn4cccn4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 40.7 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-(1H-pyrazol-1-ylmethyl)benzaldehyde (1.1 eq, 0.056 mmol, 11 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (11 mg, 41%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.62 (s, br, 4H, piperazine N(CH2)2), 3.61 (s, 2H, CH2), 3.66 (s, br, 4H, piperazine N(CH2)2), 5.41 (s, 2H, PhCH2), 6.30 (t, J=2.0 Hz, pyrazole H-4), 7.34 (d, J=8.2 Hz, 2H, phenyl H-3 & H-5), 7.39 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.49 (d, J=1.8 Hz, 1H, pyrazole H-3 or H-5), 7.78 (dt, J=7.8, 1.7 Hz, 1H, pyridine H-4), 7.86 (d, J=2.2 Hz, 1H, pyrazole H-3 or H-5), 8.14 (d, J=8.2 Hz, 2H, phenyl H-2 & H-6), 8.23 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.7, 1.7 Hz, 1H, pyridine H-6), 8.56 (d, J=1.6 Hz, 1H, pyridine H-2), 13.49 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH2:12].[CH:15](=O)[CH3:16].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:1][O:2][N:3]([CH3:14])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[NH:12][CH2:15][CH3:16]
Reactant: CC=O
Reactant: CON(C)C(=O)c1ccc(F)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNc1cc(F)ccc1C(=O)N(C)OC
Reaction time: 1.5 h

Procedure:
To a solution of N-methoxy-N-methyl-2-amino-4-fluoro-benzamide (0.20 g, 1.01 mmol), acetaldehyde (86 μL, 1.53 mmol), and AcOH (87 μL, 2.1 mmol) in dichloromethane (20 mL) was added sodium triacetoxyborohydride (430 mg, 2.03 mmol) at 5° C. The mixture was stirred for 90 minutes at the same temperature and then 40 minutes at room temperature. The reaction was quenched by adding water. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyl-4-fluoro-2-ethylamino-benzamide quantitatively.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH3:20])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>C(OCC)(=O)C.CO>[CH3:23][N:24]([CH3:26])[CH:25]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH3:20])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1cccc(N(C)S(=O)(=O)c2ccccc2)c1
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C=CC(=O)c1cccc(N(C)S(=O)(=O)c2ccccc2)c1
Yield: 84 %

Procedure:
1.25 g (4.32 mmol) of N-(3-acetyl-phenyl)-N-methyl-benzenesulfonamide were dissolved in 10 ml of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 18 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was chromatographied over silica gel using a gradient of ethyl acetate/methanol as eluent. 1.25 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl-benzenesulfonamide as a yellowish-white solid were obtained (yield 84%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:18][CH:17]=1.O>C1COCC1.[S].[P]>[C:8]1([P:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:16]2[CH:21]=[CH:20][C:19]([P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH:18][CH:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOP(=O)(OCC)c1ccc(F)cc1
Reactant: c1ccc([P-]c2ccccc2)cc1
Agent: [K+]
Agent: [P]
Agent: [S]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(OCC)c1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 19 h
Yield: 81.7 %

Procedure:
25.8 ml (12.9 mmol) of potassium diphenylphosphide solution in THF (manufacturer: Aldrich) are added dropwise at -5° C. to a solution of 3.09 g (13.2 mmol) of diethyl 4-fluorophenylphosphonate, prepared as described in Phosphorus Sulfur 1980, 9(2), 197.202, in 20.0 ml of THF. After stirring for 19 hours at 23° C., the mixture is hydrolyzed by adding 20 ml of degassed water and stirring for 15 min. After extraction with ethyl acetate, and drying the organic phase over Na2SO4, the mixture is concentrated on a rotary evaporator. 4.20 g of diethyl 4-diphenylphosphinophenylphosphonate (82% of theory) are obtained in the form of a pale yellow oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]2)(=O)=O)=CC=1.[C-:21]#[N:22].[Na+]>CS(C)=O>[F:20][C:16]1([F:19])[CH2:15][CH2:14][CH:13]([CH2:12][C:21]#[N:22])[CH2:18][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(F)(F)CC2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCC1CCC(F)(F)CC1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a solution of Example 370B (4.5 g, 15 mmol) in dimethylsulfoxide (100 mL) was added sodium cyanide (Aldrich, 2.2 g, 45 mmol). The reaction mixture was stirred at 80° C. for 14 hours, cooled to room temperature, quenched with saturated aqueous NaHCO3 (50 mL) and extracted with diethyl ether (3×50 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 50% pentane in ether) to afford the title compound. MS (ESI+) m/z 177 (M+NH4)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])[C@H:10]([OH:16])[C:11]([O:13]CC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].OO.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])[C@H:10]([OH:16])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(CC)[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)OCC
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(CC)[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)O

Procedure:
A solution of Example 236B (0.168 g, 0.51 mmol), 30% hydrogen peroxide (0.25 mL, 2.2 mmol), and lithium hydroxide monohydrate (0.042 g, 1.0 mmol) in 3:1 tetrahydrofuran/water (7 mL) was stirred in an ice bath for 3 hours, then concentrated. The residues were taken up in water and the pH adjusted to 10 with NaOH. The solution was washed twice with ether, adjusted to pH 2 with HCl, then extracted twice with ethyl acetate. The ethyl acetate extracts were dried (MgSO4), filtered, then concentrated to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[N:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1>Cl.CCOCC.CO>[F:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:20]1[CH:21]=[C:17]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([C:6]4[CH:5]=[CH:4][C:3]([N:30]5[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]5)=[C:2]([CH:7]=4)[NH2:1])[CH:9]=3)[NH:14][CH:15]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2N)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Nc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)ccc1N1CCNCC1
Yield: 7.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-amino-4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (90 mg, 0.15 mmol) was deprotected in HCl in ether/MeOH (0.2/5 ml). This afforded 5 mg (6.3% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 9.00 (s, 1H), 8.70 (s, 1H), 8.40 (s, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.90-7.80 (m, 2H), 7.63-7.61 (d, 1H), 7.45-7.35 (q, 1H), 7.20-7.00 (m, 3H), 5.45 (s, 2H), 3.12 (s, 2H), 2.76 (s, 4H). MS: m/z=467.9 (M+1), HPLC: 95.53% in method A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([OH:30])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[NH:29][C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:22]=12.O.[P:32]([O-:36])([O-:35])([OH:34])=[O:33].[K+].[K+].Cl>CC(C)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([OH:30])[CH2:15][O:16][C:17]2[C:22]3[C:23]4[C:28]([NH:29][C:21]=3[CH:20]=[CH:19][CH:18]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH2:33].[OH:34][P:32]([OH:36])([OH:35])=[O:33]
Reactant: O=P([O-])([O-])O
Agent: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=P(O)(O)O
Temperature: 32.5 °C
Reaction time: 0.17 h

Procedure:
Carvedilol (15 gm, 0.0375M), water (240 ml, 13.33M) and dipotassium hydrogen orthophosphate (6.5 g, 0.0375M) were charged in to a reactor and stirred for 10 minutes at 30-35° C. Cooled the reaction mass to 5-10° C. The pH of the reaction mass was adjusted to 4.5-5 with hydrochloric acid. The temperature was raised to 50-55° C. Acetone (51 ml, 0.7M) was added and stirred at 50-55° C. for two hours. Reaction mass was cooled to 30-35° C. and stirred for 24 hours. The reaction mass was further cooled to 5-10° C. and maintained for 1 hour. Carvedilol dihydrogen phosphate monohydrate was filtered, washed with water, suck dried and dried under vacuum at 40-45° C. till constant weight to obtain carvedilol phosphate monohydrate.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[H-].[Na+].[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1.O>CN(C=O)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:17]1[CH:18]=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccccc1Nc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-(trifluoromethyl)aniline (0.570 g, 3.54 mmol) in anhydrous DMF (4 mL), NaH (60% dispersion in mineral oil, 0.384 g, 9.6 mmol) was added portion wise at 0° C. under Argon, followed by the addition of 2,4-dichloropyrimidine (0.528 g, 3.54 mmol). The reaction mixture was slowly warmed to room temperature and stirred for a further 24 h. The solvent was removed under reduced pressure to provide a red/orange solid. The residue was slurried with water (30 mL) and solid was filtered and washed with water (10 mL×2). The dried solid was suspended in diethyl ether (5 mL) and sonicated, then filtered and washed with diethyl ether (5 mL), hexane (10 mL) to afford the title compound as a yellow solid. The solid was re-dissolved in ethyl acetate, activated charcoal was added and the mixture was stirred for 20 min at room temperature. The activated charcoal was removed by filtration through a celite/silica bed. The filtrate was collected, the solvent removed under reduced pressure to provide 5f (0.261 g, 28%) as an off-white solid. m.p. 139° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.11 (d, J=5.9 Hz, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.57-7.51 (m, 2H), 6.57 (d, J=5.9 Hz, 1H); LC-MS (ESI+) m/z 274.04 (M+H)+; HRMS (ESI+) m/z calculated for C11H8F3ClN3 (M+H)+ 274.0353. found 274.0354.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([O:19]C)[C:3]=1[O:21]C.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([Br:32])[CH:30]=[CH2:31].B(Br)(Br)Br>CN(C)C=O.C(Cl)Cl.CO>[BrH:32].[CH2:31]([N:9]1[CH2:8][CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:5]=[C:4]([OH:19])[C:3]([OH:21])=[C:2]([Cl:1])[C:12]=2[CH2:11][CH2:10]1)[CH:30]=[CH2:29]
Reactant: COc1cc2c(c(Cl)c1OC)CCNCC2c1ccccc1
Reactant: C=CCBr
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Br
Product: C=CCN1CCc2c(cc(O)c(O)c2Cl)C(c2ccccc2)C1
Reaction time: 2 h
Yield: 32 %

Procedure:
A mixture of 3.0 g (0.0095 mole) of 6-chloro-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 5.5 g (0.04 mole) of potassium carbonate and 1.15 g (0.0095 mole) of allyl bromide in 80 ml of dry dimethylformamide was refluxed for 45 minutes, filtered and the filtrate evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water and dried and concentrated to the light yellow oil (2.46 g, 78%). T.l.c. (10% methanol in chloroform) showed no starting material. The crude benzazepine was dissolved in 50 ml of dry methylene chloride and treated dropwise at -15° to -10° with 4.5 g (0.018 mole) of boron tribromide in 25 ml of dry methylene chloride. After being stirred at 0° for 2 hours, then at room temperature for one hour, the reaction was recooled, treated with excess methanol and evaporated to a tan solid. The crude product was dissolved in a little 2-propanol, diluted with ether and chilled to give 1.25 g (52%) of white 3-allyl-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide; m.p. 200°-201°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17].P(Cl)(Cl)Cl.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=[C:14]([C:13]([F:12])([F:25])[F:26])[CH:15]=1)=[O:9]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A mixture of 5-chlorosalicylic acid(6.90 g, 40 mmol), 3,5-bis(trifluoromethyl)aniline(9.16 g, 40 mmol), phosphorus trichloride(1.74 mL, 20 mmol) and toluene(80 mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate (240 mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (13.12 g, 85.5%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].Cl[CH2:14][C:15](=[O:19])[C:16]([OH:18])=[O:17].ClCC(=O)C>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:14][C:15](=[O:19])[C:16]([OH:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Reactant: O=C(O)C(=O)CCl
Agent: CC(=O)CCl
Product: O=C(O)C(=O)COc1c([N+](=O)[O-])ccc(F)c1F

Procedure:
3.9 g of 2,3-difluoro-6-nitrophenol and 3.0 g of chloropyruvic acid are reacted as described for chloroacetone in Example 8 of U.S. Pat. No. 4,382,892, to yield (2,3-difluoro-6-nitrophenoxy)-pyruvic acid. Catalytic hydrogenation (Pd/C or Raney Ni, room temperature) of the product yields in one step 7,8-difluoro-[1,4]benzoxazine-3-carboxylic acid, which is converted to its acid chloride and then is reacted first with triethylphosphite and next with diethylphosphite and a base, to form 7,8-difluoro-3-[hydroxy-bis(diethoxyphosphono)methyl]-[1,4]benzoxazine. Condensation of the latter with diethyl ethoxymethylidenemalonate, as in the above-mentioned patent, cyclization, and ester hydrolysis gives 9,10-difluoro-3-[hydroxy-bis(diethoxyphosphono)methyl]-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid, which is finally reacted with 1-methylpiperazine to yield 9-fluoro-3-[hydroxy-bis(diethoxyphosphono)methyl]-10-(4-methyl-l-piperazyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][CH2:26][NH:25][C:24]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:36](I)[CH3:37]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][CH2:26][N:25]([CH2:36][CH3:37])[C:24]=2[CH:29]=1
Reactant: CCI
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)NCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCOc2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 19.3 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (0.1 g, 0.23 mmol) in DMF (2 mL) was added potassium carbonate (0.065 g, 0.47 mmol), ethyl iodide (0.028 mL, 0.35 mmol) and stirred the solution at 20° C. for 2 h. Reaction mixture was quenched by the addition of water (2 mL), extracted with dichloromethane (3×5 mL). The organic layer was washed with water (5 mL), brine (5 mL), dried over sodium sulfate, concentrated and purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (20 mg).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1nc(O)ccc1[N+](=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 1 h
Yield: 277.5 %

Procedure:
A mixture of 2.42 gm (15.7 mMol) 6-hydroxy-3-nitro-2-picoline, 1.0 gm phosphorus pentachloride, and 0.5 mL phosphorus oxychloride was heated at 110° C. for 2.5 hours. The reaction mixture was cooled to room temperature and then an additional 0.5 gm of phosphorus pentachloride and 0.5 mL phosphorus oxychloride were added. Heating was resumed for one hour at which point the reaction mixture poured into 100 mL of an ice/water slurry. The resultant slurry is filtered and the solid dried under vacuum to provide 2.3 gm (85%) of the desired compound as a brown solid.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16](=[O:22])[CH2:17][O:18][C:19](=[O:21])[CH3:20])=[CH:6][CH:5]=1.[C:23]([O:27][C:28]([NH:30][C:31]([CH3:49])([CH3:48])[CH2:32][C:33]([NH:35][C@@H:36]1[CH2:42][CH2:41][C:40]2[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=2[NH:38][C:37]1=[O:47])=[O:34])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:19]([O:18][CH2:17][C:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:38]2[C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[CH2:41][CH2:42][C@@H:36]([NH:35][C:33](=[O:34])[CH2:32][C:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:48])[CH3:49])[C:37]2=[O:47])=[CH:9][CH:8]=1)=[O:22])(=[O:21])[CH3:20]
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reactant: CC(=O)OCC(=O)c1ccccc1-c1ccc(CCBr)cc1
Product: CC(=O)OCC(=O)c1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)CCc3ccccc32)cc1

Procedure:
Prepared from 4'-bromoethyl-2-(acetoxyacetyl) -1,1'-biphenyl and 3-t-butoxycarbonylamino-3-methyl -N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 57, Step A) by the procedure described in Example 69, Step D. 1H NMR (200 MHz,CDCl3): 1.33 (s,6H), 1.39 (s,9H), 1.87 (m,1H), 2.03 (s,3H), 2.35-2.70 (m,5H), 4.36 (s,2H), 4.51 (m,1H), 4.85 (d,15 Hz,1H), 5.28 (d,15 Hz,1H), 6.66 (m,1H), 7.1-7.6 (m,12H).
Reaction SMILES: Cl[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O-:11].[Na+].CO.O>C(O)(=O)C>[CH3:10][O:11][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: C[O-]
Reactant: Cc1ccc(O)c(Cl)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1nc(C)ccc1O
Yield: 48.1 %

Procedure:
In metal sealed tube were added 2-chloro-3-hyroxy-6-methylpyridine (1-014-02) (22.91 g) and 28% sodium methoxide/methanol solution (120 mL) and the reaction mixture was reacted at 150° C. for 3 days. To the reaction mixture was added ice and water (100 mL) and the reaction mixture was neutralized with acetic acid, and evaporated completely. The residue was purified by silica gel column chromatography (chloroform) to give the desired 2-methoxy-3-hyroxy-6-methylpyridine (1-014-03) (10.44 g, 48.1%). Furthermore, the fraction contained the starting material was reacted in sealed tube again.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2].[CH3:16][Si](C=[N+]=[N-])(C)C.[BrH:23]>C(Cl)Cl.CCCCCC.C(O)(=O)C>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[CH2:16][Br:23])=[CH:7][C:6]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)Cl)ccc1OC(C)=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Br
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(C(=O)CBr)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 1.09 g (4.6 mmol) of 4-(chlorocarbonyl)-2-methoxyphenyl acetate (as prepared in the precious step) in 10 mL of anhyd CH2Cl2 was added 10.0 mL (20.0 mmol) of a 2 M solution of trimethylsilyldiazomethane in hexane. After stirring 2 h at room temperature, the mixture was cooled (0° C.) and 3.20 mL (16.0 mmol) of 30 wt % HBr in acetic acid was added dropwise (gas evolution). After stirring 5 min, the mixture was concentrated in vacuo and rapidly chromatographed on a 10 g silica SPE column (Waters Sep-Pak) with CH2Cl2 to afford the title compound as a light yellow crystalline solid (1.28 g, 97%). 1H-NMR (300 MHz, CDCl3) δ7.63 (d, 1H, 1.9 Hz), 7.59 (dd, 1H, J=8.2, 1.9 Hz), 7.16 (d, 1H, 8.2 Hz), 4.43 (s, 2H), 3.91 (s, 3H), and 2.35 (s, 3H).