Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH3:18])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:19])[CH:4]=1.[CH:22]1(C=O)C[CH2:23]1>>[F:21][C:2]([F:1])([F:20])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH:18]4[CH2:23][CH2:22]4)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:19])[CH:4]=1
Reactant: O=CC1CC1
Reactant: CCN1CCCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc21
Product: O=c1cc(C(F)(F)F)c2cc3c(cc2[nH]1)CCCN3CC1CC1

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 192 (Structure 33 of Scheme VI, where R1═H, n=1) and cyclopropanecarboxaldehyde. 1H NMR (400 MHz, CDCl3) 11.44 (br. s, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.92 (s, 1H), 3.40 (t, 2H, J=5.6), 3.21 (d, 2H, J=6.2), 2.90 (t, 2H, J=6.3), 1.99 (m, 2H), 1.07 (m, 1H), 0.58 (m, 2H), 0.27 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:27][C:26]=1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:38][CH2:37][C:26]3[N:27]=[C:28]([C:30]4([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[O:29][C:25]=3[CH3:24])=[CH:11][CH:12]=2)[C:4]([OH:3])=[O:23])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Product: Cc1oc(C2(C)CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using the procedure of Example 63. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 2H, J=8.60 Hz), 6.93-6.84 (m, 4H), 6.69 (d, 2H, J=8.60 Hz), 4.13 (t, 2H, J=6.06 Hz), 3.22 (d, 1H, J=13.68 Hz), 3.09 (d, 1H, J=13.68 Hz), 2.98 (t, 2H, J=6.06 Hz), 2.31 (s, 3H), 2.17-2.09 (m, 2H), 1.57-1.50 (m, 4H), 1.45-1.37 (m, 4H), 1.35 (s, 3H), 1.31 (s, 3H); MS (ES+) calcd for C29H35NO5F: Found m/e 496.3 (M+1, 100%).
Reaction SMILES: O.NN.[CH3:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=2)[O:7][CH2:6]1>C(O)C.[Pd]>[CH3:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:15][C:16]2[N:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[O:7][CH2:6]1
Reactant: CC1COc2cccc(Oc3ccc([N+](=O)[O-])cn3)c2C1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC1COc2cccc(Oc3ccc(N)cn3)c2C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
In a 50 ml round-bottomed flask 2-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-5-nitropyridine (Intermediate 118, 181 mg) was dissolved in ethanol (10 ml) to give a pale yellow solution. Pd/C (33.0 mg, 0.031 mmol) and hydrazine hydrate (0.030 ml, 0.310 mmol) were added. The reaction mixture was stirred at 90° C. After 1 hour, the reaction mixture was filtered and evaporated under vacuum to give the title compound (131.4 mg).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([O:7]CC)=O)C.[CH3:11][N:12]([C:14]([NH2:16])=[S:15])[NH2:13].C[O-].[Na+].CO>C(Cl)Cl>[CH3:11][N:12]1[C:14](=[S:15])[NH:16][C:4](=[O:3])[C:5](=[O:7])[NH:13]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CN(N)C(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cn1[nH]c(=O)c(=O)[nH]c1=S
Temperature: 60 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
Under anhydrous condition, 35 g of diethyloxalate is added, dropwise, to a vigorously stirred solution of 21 g of 2-methyl-3-thiosemicarbazide, 32.4 g of fresh sodium methoxide, and 750 ml of methyl alcohol. The resulting suspension is heated at 60° C. for 4 hours, stirred overnight at room temperature, and heated at 70° C. for 15 hours. The white suspension is cooled to room temperature, 200 ml of ice water is added and the reaction concentrated in vacuo. The residue is cooled to 0° C. and made acidic with 2N hydrochloric acid. The reaction mixture is concentrated, ethyl alcohol is added and the suspension is heated to boiling. The white precipitate is collected, washed with hexane and dried to give 11 g of the crude product. Eight grams of the crude product is heated in methylene chloride and filtered while hot. The collected solid is resuspended in methyl alcohol and a solution of 4N potassium-2-ethyl hexanoate is added. The mixture is cooled to 0° C. and the precipitate collected. The solid is dissolved in water, filtered, and 2N hydrochloric acid is added to the clear 0° C. solution. The resulting precipitate is collected and dried to give 4.1 g of the pure product.
Reaction SMILES: C1(C)C=CC(S(OCCCCCC[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)(=O)=O)=CC=1.[OH-:31].[K+].[CH:33]1([CH2:37][OH:38])[CH2:36][CH2:35][CH2:34]1>CS(C)=O>[Br:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:19]=[CH:18][C:17]([O:31][CH2:21][CH2:22][CH2:17][CH2:18][CH2:19][CH2:20][O:38][CH2:37][CH:33]3[CH2:36][CH2:35][CH2:34]3)=[CH:22][CH:21]=2)=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCc2ccc(-c3ccc(Br)cc3)cc2)cc1
Reactant: OCC1CCC1
Reactant: [OH-]
Agent: [K+]
Solvent: CS(C)=O
Product: Brc1ccc(-c2ccc(OCCCCCCOCC3CCC3)cc2)cc1
Reaction time: 1 h

Procedure:
A solution of (4′-Bromobiphenyl-4-yl)hexyl toluene-p-sulphonate (2.50 g, 5.0 mmol) from step 2 in DMSO (50 ml) was cooled to −5° C. and potassium hydroxide powder (Fluka, 1.03 g, 0.018 mol) was added and the mixture was stirred using a mechanical stirrer, a solution of cyclobutylmethanol (0.80 g, 10.0 mmol) in DMSO (15 ml) was added dropwise. The reaction mixture was kept at −5° C. for 1 h and then removed from the cooling bath for a further 2 h. The product was extracted in hexane (150 ml) and washed with water in order to remove all traces of DMSO. Hexane was removed under reduced pressure and the residue was purified by column chromatography [DCM-hexane, 1:6] to give a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[NH:10][C@@H:11]([C:21](=[O:32])[NH:22][C@H:23]([CH2:27][O:28][CH2:29][CH:30]=C)[CH:24]([CH3:26])[CH3:25])[CH2:12][C:13]1[N:14]=[CH:15][N:16]([CH2:18][CH:19]=C)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH2:1]([O:8][C:9](=[O:33])[NH:10][C@@H:11]1[CH2:12][C:13]2=[CH:17][N:16]([CH:15]=[N:14]2)[CH2:18][CH:19]=[CH:30][CH2:29][O:28][CH2:27][C@H:23]([CH:24]([CH3:25])[CH3:26])[NH:22][C:21]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC[C@@H](NC(=O)[C@@H](Cc1cn(CC=C)cn1)NC(=O)OCc1ccccc1)C(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: CC(C)[C@H]1COCC=CCn2cnc(c2)C[C@@H](NC(=O)OCc2ccccc2)C(=O)N1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
A solution of 0.735 g (1.62 mmol) of benzyl[(R)-2-(1-allyl-1H-imidazol-4-yl)-1-((S)-1-allyloxymethyl-2-methylpropylcarbamoyl)ethyl]carbamate in 370 ml of dichloromethane was mixed with 0.210 g (0.24 mmol) of benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium (Grubbs II catalyst) and stirred at RT. The mixture was stirred at RT for several days with repeated addition of Grubbs II catalyst until starting material was no longer present (LC/MS). The mixture was concentrated and the residue was chromatographed on silica gel (dichloromethane/methanol 99:1→9:1). 0.506 g of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:8]=[C:9](F)[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[CH3:16][CH2:17][O-:18].[Na+]>C(O)C>[NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:8]=[C:9]([O:18][CH2:17][CH3:16])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: Nc1c(F)c(F)cc(C(=O)O)c1[N+](=O)[O-]
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc(C(=O)O)c([N+](=O)[O-])c(N)c1F

Procedure:
1.2 g (5.5 mmol) of 3-amino-4,5-difluoro-2-nitro-benzoic acid was heated with excess 21% NaOEt in ethanol at 90° C. for 6 h to yield 3-amino-5-ethoxy-4-fluoro-2-nitro-benzoic acid. LCMS: 245 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[C:10]=2[CH3:28])[CH2:8][CH2:7]1.[OH-].[Na+]>CO.CCOCC.CCCCCC>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:11]2[C:12]3[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9]([C:6]3([CH2:5][CH2:4][C:3]([OH:29])=[O:2])[CH2:8][CH2:7]3)=[C:10]2[CH3:28])=[CH:22][CH:23]=1
Reactant: COC(=O)CCC1(c2c(C)n(Cc3ccc(Br)cc3)c3ccc(OC)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccc2c(c1)c(C1(CCC(=O)O)CC1)c(C)n2Cc1ccc(Br)cc1
Yield: 75.4 %

Procedure:
To a solution of ester from Step 11 (150 mg, 0.33 mmol) in 5 mL MeOH was added 2N NaOH (0.5 mL, 1 mmol). The reaction mixture was heated to reflux for 3 h then cooled and partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was filtered through a plug of silicic acid and the solid obtained was swished in (1: 1 ) Et2O-hexane. Collection of the solid provided 110 mg of the title compound.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl.Cl.[C:12](=[NH:20])([O:18][CH3:19])[CH2:13][C:14](=[NH:17])[O:15][CH3:16].[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](O)=O)([O-:23])=[O:22].C(C1NC=CN=1)(C1NC=CN=1)=O>ClCCl.CC(O)C>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([O:18][CH3:19])[N:20]=[C:31]([CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N+:21]([O-:23])=[O:22])[N:17]=1
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=N)CC(=N)OC
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC)nc(Cc2ccccc2[N+](=O)[O-])n1
Temperature: -40 °C
Reaction time: 0.42 h
Yield: 32.9 %

Procedure:
Ethyl diisopropylamine (240 ml) was added dropwise to a stirred suspension of dimethyl malonimidate dihydrochloride (73.2 g) in dichloromethane (400 ml) at -40° C. under nitrogen, and the mixture was stirred at -40° C. for 25 minutes to give suspension A. 2-Nitrophenylacetic acid (65.16 g) was added portionwise to a stirred suspension of carbonyl diimidazole (53.3 g) in dichloromethane (400 ml) at room temperature. The resulting solution was stirred for 10 minutes and was added dropwise over 30 minutes to the suspension A at -40° C. The mixture was stirred at -40° C. for a further 45 minutes and then at room temperature overnight, after which the solution was washed with water (400 ml), 2N HCl (400 ml) and saturated sodium bicarbonate solution (400 ml), dried and evaporated to give an orange solid. It was then stirred with propan-2-ol (50 ml) for 10 minutes and filtered. The solid was washed with a further 50 ml of propan-2 -ol and then dried to give 32.6 g of the desired product as a yellow solid, mp 92°-93° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].CI.[C:30](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)(=[O:17])=[O:18])[CH3:30])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1ccc(F)c(Cl)c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
To a solution of [(R)-4-(3-chloro-4-fluoro-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (150 mg, 0.36 mmol, prepared as described in example 4-1, 1st step) in acetonitrile (10 mL) was added methyl iodide (154 mg, 1.1 mmol) and potassium carbonate (151 mg, 1.1 mmol). The reaction mixture was stirred at 65° C. for 5 hours, then cooled to room temperature and filtered through a glass funnel. The filtrate was evaporated under reduced pressure and purified by column chromatography (gradient elution, 0-10% methanol in dichloromethane) to afford {(R)-4-[(3-chloro-4-fluoro-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (150 mg, 96%) as a yellow solid. MS cald for C18H21ClN3O4S 429, obsd. (ESI+) [(M+H)+]: 430.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=2)=[CH2:9])[CH:5]=[CH:6][CH:7]=1.[C:17](=[O:20])([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][O:26]C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:26][CH2:25][CH2:24][O:20][CH3:17])=[CH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCBr
Reactant: O=C([O-])[O-]
Reactant: C=C(c1ccc(O)cc1)c1cccc(Br)c1
Agent: [Cs+]
Solvent: O
Product: C=C(c1cccc(Br)c1)c1ccccc1OCCOC
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 4-[1-(3-bromo-phenyl)-vinyl]-phenol (1.2 g, 4.0 mmol, 1 eq) N,N-dimethylformamide (10 mL), and cesium carbonate (2.8 g, 8.0 mmol, 2.0 eq) was stirred at room temperature then 1-bromo-2-methoxy-ethane (0.5 mL, 1.0 eq) was added. The mixture was heated to 50° C. overnight, cooled to room temperature and treated with water (100 mL). The reaction was extracted with dichloromethane, dried (sodium sulfate) and concentrated in vacuo. The crude was purified by flash chromatography eluting with cyclohexane to afford the title compound as a colorless oil (1.7 g, 85%);
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17].Cl>O1CCCC1.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([NH:5][C:16](=[O:17])[O:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(O)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 11 %

Procedure:
A mixture of 3-hydroxyaniline (2.0 g) and pyridine (3.3 ml) in tetrahydrofuran was stirred at 0° C. and then p-nitrophenyl chloroformate (3.88 g) was added, stirred at the same temperature for 5 hours. Ethyl acetate and 1N HCl were added to the reaction mixture, and the organic layer was separated, washed with water, dried over magnesium sulfate, and evaporated in vacuo. The yellow powder was washed with ethyl acetate to afford 4-nitro-phenyl N-(3-hydroxyphenyl)carbamate (554 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NCCC(=O)O
Product: O=C(O)CCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 90.3 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and β-alanine (0.115 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.31 g (90%) 141 as a very pale yellow powder: mp=206-208° C.; Rf0.84 (A): Rf0.81 (B): Rf0.55 (D): IR (cm−1): 2800-3125 (OH), 3109 (C═CH), 2646 (C—H), 1780 (C═O), 1718 (bs, C═O), 1621 (C═C), 1536 (N═O), 1441 (C═C), 1395 (C—O), 1346 (N═O), 1228 (C—O), 724 (C═CH); MS m/z (rel intensity) 263 (100), 191 (36).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.F[B-](F)(F)F.ClC1C=CC([N+]#N)=CN=1.OO.FC(F)(F)C(O)=[O:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N+:3]=1[O-:28]
Reactant: O=C(O)C(F)(F)F
Reactant: Fc1ccc(Cl)nc1
Agent: F[B-](F)(F)F
Agent: N#[N+]c1ccc(Cl)nc1
Agent: OO
Product: [O-][n+]1cc(F)ccc1Cl
Yield: 70 %

Procedure:
2-Chloro-5-fluoropyridine (9), a highly volatile substance, was synthesized from thermolysis of 2-chloro-5-pyridinediazonium tetrafluoroborate (8). Hand, E. S.; Baker, D. C. Synthesis 1989, 905-908. The isolation of 9 by the literature procedure was very complicated, in that it included repeated extractions, repeated distillations, treatment with sulfuric acid and sodium hydroxide, and steam distillation. In our hands, the reported yield of 70% was difficult to obtain after these operations. To improve upon these complicated procedures, following the thermolysis of compound 8, the reaction mixture was directly treated with 50% hydrogen peroxide and trifluoroacetic acid to give 2-chloro-5-fluoropyridine-N-oxide (10), which was easily isolated, with a total yield of 73%. Nitration of 10, followed by catalytic hydrogenation of the resulting 2-chloro-5-fluoro-4-nitropyridine-1-oxide (11) removed the N-oxide function, as well as reduced the nitro group to give the desired 4-amino-2-chloro-5-fluoropyridine (12). N-Oxidation of commercially available 2,5-dichloropyridine (13), followed by nitration and reduction yielded 4-amino-2,5-dichloropyridine (16).
Reaction SMILES: Cl.C(O[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])C.C([O-])(=O)C.[NH4+:18].O.[OH-].[NH4+]>C(N(CC)CC)C.C(OCC)(=O)C>[N+:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[NH2:18])([O-:13])=[O:12]
Reactant: [NH4+]
Reactant: CCOc1ccncc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1ccncc1[N+](=O)[O-]
Temperature: 4 °C
Yield: 86.6 %

Procedure:
A 500 ml 3-neck round bottom flask equipped with a condenser, thermometer and mechanical stirrer was charged with 78.4 g (0.383 mol) of 4-ethoxy-3-nitropyridine hydrochloride, 118.1 g (1.53 mol) of ammonium acetate and 183 ml of water. The stirred reaction mixture was refluxed for 71/2 hours and the progress of the reaction was followed by thin layer chromatography employing a 10:1 ethyl acetate:triethylamine solvent system. The reaction flask was chilled to approximately 4° C. after the pH of the mixture was adjusted from 5.2 to 8.1 with 60 ml of concentrated ammonium hydroxide. The yellow precipitate was collected by filtration, washed twice with chilled water and dried under vacuum at 50° C. for 10 hours. A total dry weight of 46.15 g (86.6% yield) of 3-nitro-4-aminopyridine was obtained. The product was verified by NMR and compared to an authentic sample.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=2)[N:4]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ccc(Cl)nn1
Solvent: CCO
Product: CCOC(=O)Cc1cn2nc(Cl)ccc2n1
Yield: 61.3 %

Procedure:
After 11.2 g of 3-amino-6-chloropyridazine was suspended in 150 mL of ethanol, 28.6 g of ethyl 4-chloroacetoacetate was added thereto and heated under reflux for 24 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was adjusted to pH 7 by the addition of an aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with a saline solution and dried over magnesium sulfate. After concentration under reduced pressure. The residue was subjected to silica gel chromatography to be eluted with hexane:ethyl acetate (2:3). The desired fraction was collected to provide 12.7 g of the title compound.
Reaction SMILES: P(OCC)(OCC)(OCC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH:26][CH2:27][CH2:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH:40]=O)[C:35]#[N:36])(=[O:31])=[O:30].[F:42][C:43]([F:55])([F:54])[C:44]1[CH:45]=[C:46]([NH:50][C:51]([NH2:53])=[O:52])[CH:47]=[CH:48][CH:49]=1.[C:56]([O:62][CH2:63][CH:64]=[CH2:65])(=[O:61])[CH2:57][C:58]([CH3:60])=O>CC(OC)(C)C>[C:35]([C:34]1[CH:37]=[CH:38][C:39]([CH:40]2[C:57]([C:56]([O:62][CH2:63][CH:64]=[CH2:65])=[O:61])=[C:58]([CH3:60])[N:50]([C:46]3[CH:47]=[CH:48][CH:49]=[C:44]([C:43]([F:54])([F:55])[F:42])[CH:45]=3)[C:51](=[O:52])[NH:53]2)=[C:32]([S:29]([CH2:28][CH2:27][OH:26])(=[O:30])=[O:31])[CH:33]=1)#[N:36]
Reactant: C=CCOC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)c(S(=O)(=O)CCO)c1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOP(=O)(OCC)OCC
Solvent: COC(C)(C)C
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(=O)(=O)CCO
Temperature: 90 °C

Procedure:
The reaction was carried out under argon. Triethyl phosphate (1.43 g, 7.9 mmol; 1.2 eq.) and diphosphorus pentoxide (0.745 g; 0.8 eq.) were stirred at 40° C. overnight. The mixture was then diluted with MTBE (35 ml), and 3-[(2-hydroxyethyl)sulfonyl]-4-formylbenzonitrile (1.57 g, 6.6 mmol), 1-[3-(trifluoromethyl)phenyl]urea (1.34 g, 6.6 mmol) and allyl acetoacetate (1.4 g, 9.84 mmol; 1.5 eq.) were added. The mixture was stirred under reflux for 2 h. The reaction mixture was then concentrated by distillative removal of MTBE and subsequently heated at 90° C. for a further 5 h. For work-up, residual solvent was removed under reduced pressure and the residue was taken up in ethyl acetate (250 ml). The organic phase was washed with saturated sodium chloride solution (3×50 ml), dried over solid sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 2:3). The title compound was obtained as a colorless solid (1.22 g, 23% of theory).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6](#[N:9])[CH:7]=[CH2:8].C=O.C#N.C=O.C#N.S([O-])(O)=O>>[C:6]([CH2:7][CH2:8][NH:1][CH2:2][CH2:3][CH2:4][OH:5])#[N:9]
Reactant: NCCCO
Reactant: C=CC#N
Agent: C#N
Agent: C=O
Agent: O=S([O-])O
Product: N#CCCNCCCO

Procedure:
75 grams (1 mole) of 3-amino-propanol were treated with 53 grams (1 mole) of acrylonitrile within one hour at 25° C. The mixture was allowed to react further for 1 hour at 40° C. The thus obtained reaction product (128 grams) was directly reacted further with formaldehyde/hydrocyanic acid or formaldehyde/alkali salt of hydrocyanic acid in the presence of alkali hydrogen sulfite.
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[CH:8][C:7](=[O:11])[C:6]([C:12]([OH:14])=[O:13])=[CH:5]1)([CH3:3])[CH3:2].[Br:15]Br.ClCCl>C(O)(=O)C.O>[Br:15][C:8]1[C:7](=[O:11])[C:6]([C:12]([OH:14])=[O:13])=[CH:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:9]=1[CH3:10]
Reactant: BrBr
Reactant: Cc1cc(=O)c(C(=O)O)cn1C(C)C
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1b, 1.50 g, 6.92 mmol based on 90% purity) in glacial acetic acid (10 ml) is added at room temperature bromine (0.60 mL, 11.7 mmol). After stirring for 3 d at room temperature, additional bromine (1.00 mL, 19.5 mmol) is added to the reaction mixture and stirring is continued for 2 h at room temperature. The reaction mixture is diluted with water. Upon addition of dichloromethane a precipitate forms which is filtered off and dried. Yield: 2.55 g; ESI mass spectrum: [M+H]+=274 (bromine isotope pattern); r.t. HPLC: 0.76 min (Z002_002).