Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=2)=O)=[CH:9][CH:8]=1)[CH3:4].Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[OH:35]/[N:34]=[C:15](/[C:17]1[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=1)\[CH2:14][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([C:6]([NH:5][C@@H:3]([CH3:4])[CH2:2][OH:1])=[O:32])=[CH:12][CH:11]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@@H](C)CO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@@H](C)CO)cc1

Procedure:
In analogy to example 151, step 3, N—((S)-1-hydroxypropan-2-yl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid, MS (ESI+): m/z=448.2 [M+H]+.
Reaction SMILES: [I-:1].Cl[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH3:9].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(N(C(C)C)CC)(C)C>C(#N)C>[I-:1].[N:10]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=2[CH3:9])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: C[n+]1ccccc1Cl
Reactant: c1c[nH]cn1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[n+]1ccccc1-n1ccnc1

Procedure:
2-Chloro-1-methylpyridinium iodide (9.43 g), imidazole (2.45 g) and diisopropylethylamine (4.77 g) were added to acetonitrile (150 ml) and the mixture refluxed for 2 hours. The product was filtered off from the chilled solution and dried. Yield, 6 g.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH2:14](O)[CH3:15]>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:14][CH3:15])=[O:5]
Reactant: CCO
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Agent: Cl
Product: CCOC(=O)c1cc(Cl)cc(Cl)c1N

Procedure:
A mixture of 50 parts of 2-amino-3,5-dichlorobenzoic acid and 240 parts of ethanol is saturated with gaseous hydrogen chloride. The whole is stirred and refluxed for 10 hours. The reaction mixture is allowed to cool and the solvent is evaporated. To the solid residue are added water and sodium hydroxide. The precipitated product is filtered off and dried, yielding 25 parts of ethyl 2-amino-3,5-dichlorobenzoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15]3=[O:26])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(N(CC)CC)C>[C:27]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:9][CH:8]=2)[C:15](=[O:26])[CH:16]1[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)CC1NCCN(CCc2c[nH]c3cc(OC)ccc23)C1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1C(=O)N(CCc2c[nH]c3cc(OC)ccc23)CCN1C(=O)c1ccccc1

Procedure:
Using the procedure of Step D of Example 1, 14 g of the product of Step C, 8.2 ml of triethylamine and 4.5 ml of benzoyl chloride were reacted to obtain 18 g of the expected product.
Reaction SMILES: [C:1]([O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:9]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[C:1]([O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([OH:16])=[O:15])[CH2:9]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)OC[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)OC[C@H]1CCCN(C(=O)O)C1

Procedure:
170 mg of dimethylaminopyridine and 3.4 mg of pyridine are added to 3.0 g of t-butyl (S)-3-hydroxy-1-piperidine-carboxylate. 1.66 ml of isobutyryl chloride are added dropwise thereto. The reaction mixture is then concentrated. The residue is taken up in ether and the ether phase is washed in succession with 20 ml of citric acid, water, sodium bicarbonate solution and water. After drying and evaporation of the ether phase there are obtained 3.9 g of t-butyl (S)-3-isobutyroxymethyl-1-piperidinecarboxylate, Rf=0.87 (ether). 3.09 g of this ester are dissolved in 80 ml of methylene chloride and treated with 20 ml of trifluoroacetic acid. After stirring for 30 minutes the solution o is concentrated. 30 ml of methanol are added to the residue and saturated sodium bicarbonate solution is then added dropwise. The aqueous phase is extracted with methylene chloride and the methylene chloride extracts are dried and concentrated. There are obtained 2.82 g of (S)-3-iso-butyroxymethyl-1-piperidinecarboxylic acid trifluoroacetic acid salt, Rf=0.4 (Takeda solution).
Reaction SMILES: [N+:1]([CH2:4][C:5]1(O)[CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6]1)([O-:3])=[O:2].C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[N+:1]([CH:4]=[C:5]1[CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])CC1(O)COCCOC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])C=C1COCCOC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A stirred mixture of 6-nitromethyl-[1,4]dioxepan-6-ol (0.74 g, 4.18 mmol) and triethylamine (1.86 g, 2.56 mL, 18.4 mmol) in dichloromethane (20 mL), under nitrogen, was cooled to −78° C. and methanesulfonyl chloride (1.43 g, 970 μL, 12.5 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes and then quenched with saturated ammonium chloride solution. The mixture was removed from the cooling bath and allowed to warm to ambient temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 3:1 to 1:1 to give the title compound (512 mg, 77%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 3.81-3.90 (m, 4H), 4.36 (d, J=0.5 Hz, 2H), 5.04 (d, J=2.5 Hz, 2H), 7.02 (t, J=2.5 Hz, 1H). LCMS (m/z) 182.1.0 [M+Na], Tr=1.04 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][OH:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:14]([CH:15]=[O:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ncc(CO)c(OCc2ccccc2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CSc1ncc(C=O)c(OCc2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of (4-(benzyloxy)-2-(methylthio)pyrimidin-5-yl)methanol (S26, 818 mg) in toluene (30 mL), manganese dioxide (8.13 g) was added at room temperature, and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and then the insoluble matter was removed by filtration through Cerite. The solvent was evaporated under reduced pressure to obtain oily 4-(benzyloxy)-2-(methylthio)pyrimidine-5-carbaldehyde (S20, 666 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:32]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Cl:32])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:28]=[CH:27][C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1[nH]c(=O)c2cc(Oc3ccc4c(c3)OCO4)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCOC(=O)c1nc(Cl)c2cc(Oc3ccc4c(c3)OCO4)ccc2c1O

Procedure:
Prepared in analogy to example 31f from 7-(benzo[1,3]dioxol-5-yloxy)-4-hydroxy-1-oxo-1,2-dihydro-isoquinoline-3-carboxylic acid butyl ester and POCl3. 1H NMR (200 MHz, CDCl3): δ (ppm)=11.89 (s, 1H), 8.35 (d, 1H, J=9.2 Hz), 7.57 (d, 1H, J=1.9 Hz), 7.50 (m, 1H), 6.83 (d, 1H, J=7.8 Hz), 6.65-6.56 (m, 2H), 6.03 (s, 2H), 4.47 (t, 2H, J=7.1 Hz), 1.9-1.4 (m, 4H), 0.99 (t, 3H, J=7.3 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](Cl)=[O:37]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([C:27]3[CH:28]=[CH:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:26]=3)=[O:37])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccc2ccccc2n1
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=O)c1ccc2ccccc2n1

Procedure:
According to the general method of Example 61, 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine and quinoline-2-carbonyl chloride were combined to provide N2-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-quinolinecarboxamide as an off white crystalline solid, m.p. 81.1-83.9° C. 1H NMR (300 MHz, DMSO-d6) δ 8.90 (t, J=6.0 Hz, 1H), 8.55 (d, J=8.5 Hz, 1H), 8.12-8.07 (m, 4H), 7.90-7.84 (m, 1H), 7.75-7.54 (m, 7H), 7.36 (t, J=7.5 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 6.70 (broad s, 2H), 4.61 (m, 2H), 3.23 (m, 2H), 1.88 (m, 2H), 1.49 (m, 2H); MS (CI) m/e 487 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[N:12]=[C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26]CC4C=CC=CC=4)=[O:25])=[CH:20][CH:19]=3)[C:10]=2[F:34])=[CH:6][C:5]=1[O:37]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([F:16])[N:12]=[C:11]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([OH:26])=[O:25])=[CH:22][CH:23]=3)[C:10]=2[F:34])=[CH:6][C:5]=1[OH:37]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)c1ccc(Oc2nc(F)c(F)c(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)c2F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2c(F)c(F)nc(Oc3ccc(C(=O)O)cc3)c2F)cc1O
Reaction time: 8 h
Yield: 91 %

Procedure:
40 g of the 4-(4-nitro-3-benzyloxyphenoxy)-2-(4-benzyloxycarbonylphenoxy)-3,5,6-trifluoropyridine prepared as described in Example 7 (0.066 mol) are dissolved in 600 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 4 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated using hydrogen at a pressure of 1 bar at room temperature in an autoclave with vigorous stirring; the reaction is terminated after 3 days. The orange solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates out in crystalline form. The reaction product is then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 91%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][C:11]3=[N:21][N:22]([CH3:24])[CH:23]=[C:10]3[C:9]=2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:5]=[CH:4][N:3]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:9]2[C:10]3[C:11](=[N:21][N:22]([CH3:24])[CH:23]=3)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:40])=[O:41])=[CH:35][CH:34]=3)[CH:7]=2)=[CH:26][CH:27]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: Cn1cc2c(-c3ccc(F)cc3)c(-c3ccnc(Cl)c3)c(-c3ccc(F)cc3)nc2n1
Product: Cn1cc2c(-c3ccc(F)cc3)c(-c3ccnc(Nc4ccc(S(N)(=O)=O)cc4)c3)c(-c3ccc(F)cc3)nc2n1
Temperature: 190 °C
Yield: 17.6 %

Procedure:
A mixture of 5-(2-chloropyridin-4-yl)-4,6-bis(4-fluorophenyl)-2-methylpyrazolo[3,4-b]pyridine (100 mg, 0.23 mmol, obtained in example 190) and 4-aminobenzenesulfonamide (46 mg, 0.27 mmol) was heated at 190° C. overnight. It was allowed to cool and the crude product obtained was purified by chromatography on silica gel using EtOAc as eluent, to afford 23 mg of the desired compound (yield: 17%).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[F:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.Cl>>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:2]([CH3:1])[CH2:3]3)[CH2:20][CH2:19]2)=[CH:25][CH:26]=1
Reactant: O=C1CCN(CCc2ccc(F)cc2)CC1
Reactant: CC1CNc2ccccc21
Agent: Cl
Product: CC1CN(C2CCN(CCc3ccc(F)cc3)CC2)c2ccccc21
Yield: 75.6 %

Procedure:
3-Methylindoline (0.2 g) and 1-(4-fluorophenethyl)-4-piperidone (0.50 g) were treated as in Example 16 to give the title compound (0.384 g) as a pale yellow oil (yield: 7.0.7%) Next, hydrochloric acid was added thereto to give a salt followed by recrystallization from ethanol. Thus the hydrochloride (0.314 g) of the title compound was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:16][CH3:17])=[N:4][N:3]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:21][CH2:20]1>>[CH3:15][O:14][C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[C:11]2[C:6]=1[C:5]([CH2:16][CH3:17])=[N:4][N:3]=[C:2]2[NH:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:23][CH2:24]1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: CCc1nnc(Cl)c2cc(OC)cc(OC)c12
Product: CCc1nnc(NC2CCN(Cc3ccc4ccccc4c3)CC2)c2cc(OC)cc(OC)c12

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-5,7-dimethoxy-4-ethylphthalazine with 4-amino-1-(naphthalen-2-yl-methyl)piperidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:28])[CH2:6][CH2:7]2)=[CH:18][CH:17]=1
Reactant: O=C=NC1CCCCC1
Reactant: NCCCN1CCCN(Cc2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: O=C(NCCCN1CCCN(Cc2ccc(Cl)cc2)CC1)NC1CCCCC1

Procedure:
A solution of 1-(3-aminopropyl)-4-(4-chlorobenzyl)-homopiperazine (2.16 g; 7.7 mmole) in methylene chloride (30 ml) was stirred at room temperature with cyclohexyl isocyanate (1.05 g; 8.5 mmole) for one hour. The reaction mixture was concentrated under reduced pressure to an oil which was chromatographed on silica gel (methylene chloride/methanol/ammonium hydroxide: 97/2.5/0.5) to yield 1-{3-[4-(4-chlorobenzyl)homopiperazin-1-yl]propyl}-3-cyclohexylurea as a colorless oil. This oil was dissolved in ether and precipitated with ethereal hydrogen chloride to provide the title compound (2.25 g; 61% yield) as a white crystalline solid, m.p. 167°-175° C. (dec.).
Reaction SMILES: C([Li])CCC.C(O)(C)(C)C.[CH2:11]([O:13][C:14]([NH:16][C:17]1[CH:37]=[CH:36][C:20]([C:21]([C:23]2[N:24]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:25]=[CH:26][CH:27]=2)=[O:22])=[CH:19][CH:18]=1)=[O:15])[CH3:12].[CH3:38][OH:39]>C1COCC1>[OH:39][CH2:38][C@@H:11]1[O:13][C:14](=[O:15])[N:16]([C:17]2[CH:37]=[CH:36][C:20]([C:21]([C:23]3[N:24]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:25]=[CH:26][CH:27]=3)=[O:22])=[CH:19][CH:18]=2)[CH2:12]1
Reactant: CO
Reactant: CCOC(=O)Nc1ccc(C(=O)c2cccn2COCC[Si](C)(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C[Si](C)(C)CCOCn1cccc1C(=O)c1ccc(N2C[C@H](CO)OC2=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (4.6 ml. of 1.6 M solution in THF, 7.36 mM) was added to a stirred solution of t-butanol (0.505 g) in dry THF at −20° C. under nitrogen and the mixture stirred for 20 minutes. The temperature was lowered to −60° C. and 2-(4-ethoxycarbonylaminobenzoyl)-1-(2-trimethylsilylethoxymethyl)pyrrole (2.2 g. 5.67 mM) added over 15 minutes. The mixture was stirred for 50 minutes and a solution of R-(−) glycidyl butyrate (0.9 g. 6.25 mM) in dry THF (5 ml) added. The mixture was allowed to warm to ambient temperature and stirred for 24 hours. MeOH (20 ml) was added and the solution evaporated and the residue partitioned between EtOAc and water The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using 2% MeOH/dichloromethane as eluant, to give 5(R)-hydroxymethyl-N-(4-[1-(2-trimethylsilylethoxymethyl)pyrrol-2-ylcarbonyl]phenyl)oxazolidin-2-one as an oil (0.77 g; MS: 417 (MM−)).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][C:11]=1[F:15])=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCCl)c1ccc(F)cc1F
Temperature: 0 °C
Yield: 85.2 %

Procedure:
255 g (1.81 mols) of 4-chlorobutyryl chloride are added dropwise to a mixture of 200 g (1.75 mols) of 1,3-difluorobenzene and 256 g (1.92 mols) of anhydrous aluminum chloride at room temperature, while stirring. The mixture is stirred at 30° C. for 4 hours and then poured onto 1,200 g of ice. 1,200 ml of methylene chloride are added, the organic phase is separated off, the aqueous phase is extracted with methylene chloride and the combined organic phases are washed with water, dried over sodium sulphate and concentrated by stripping off the solvent under reduced pressure. The residue which remains is distilled. 326 g (85% of theory) of 2,4-difluorophenyl 3-chloropropyl ketone are obtained in this manner.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].OS(O)(=O)=O.[N+:14]([O-])([OH:16])=[O:15]>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: [O-][n+]1ccccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Temperature: 0 °C
Yield: 56 %

Procedure:
2-Chloro-pyridine-1-oxide (10 g) is cooled in an ice bath and treated with concentrated H2SO4 (15 ml), followed by the dropwise addition of a mixture of concentrated H2SO4 (15 ml) and fuming HNO3 (27 ml, s.g. 1.5) over a 70 minute period. The acidic solution is heated in a steam bath for 2.5 hours, then allowed to reach room temperature and poured onto ice water (600 ml), stirring being continued until all the ice has melted. The resultant solid is filtered off and dissolved in hot chloroform, the solution being dried and the solvent evaporated in vacuo to give a yellow solid. The aqueous filtrate obtained after the removal of the original solid is neutralised with saturated aqueous Na2CO3 and extracted continuously with chloroform, the extract being dried and evaporated in vacuo to yield a yellow solid. The two yellow solids are combined and recrystallised from ethanol to give 2-chloro-4-nitro-pyridine-1-oxide as yellow crystals (7.46 g, 56%).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[CH3:13][NH2:14].O1CCCC1>O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:14][CH3:13])=[O:3]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1ccccc1N
Reaction time: 1 h
Yield: 92 %

Procedure:
To a suspension of 16.3 g (100 mmol) of isatoic anhydride in 100 mL of H2O is added portionwise 100 mL of 2N methylamine-tetrahydrofuran solution (200 mmol) at room temperature. The reaction mixture is stirred for 1 hour and then extracted with AcOEt. The organic layer is washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure to give 13.79 g of desired product, 2-amino-N-methyl-benzamide (92 mmol, 92%) as colorless solid.
Reaction SMILES: [C:1]([NH:6][N:7]=[C:8]([CH3:17])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Cl:18]Cl.[OH-].[Na+].Cl.C(N(CC)CC)C.Cl>C(N(CC)CC)C.CCCCC>[C:1]([N:6]=[N:7][C:8]([Cl:18])([CH3:17])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: ClCl
Reactant: C=CCOC(=O)CCC(C)=NNC(C)(C)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: C=CCOC(=O)CCC(C)(Cl)N=NC(C)(C)CC
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a 1 liter 3-neck round bottom flask, equipped with a mechanical stirrer, thermometer, chlorine inlet tube and condenser was added 96.0 grams (0.4 mole) of allyl levulinate t-amylhydrazone, 400 mls of pentane and 41.5 grams of triethylamine. The resulting solution was cooled to 5° C. and and with stirring 28.4 grams (0.4 mole) of chlorine was slowly added over 30 minutes, holding the temperature at 5° to 15° C. After the addition was complete the mixture was stirred for 10 minutes at 10° C. before adding 164 grams of 10% NaOH to neutralize the triethylamine hydrochloride that had formed. The mixture was stirred until the hydrochloride dissolved and then the aqueous layer was separated. The pentane layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane and triethylamine stripped off on a rotary evaporator under reduced pressure. The residue was a yellow liquid weighing 109 grams (99% crude yield). The product was used as an intermediate in preparing the following azo compounds.
Reaction SMILES: C[O:2][CH:3](Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.[F:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>ClCCl>[F:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:3]=[O:2])=[CH:14][CH:13]=1
Reactant: COC(Cl)Cl
Reactant: Fc1cccc2ccccc12
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc(F)c2ccccc12
Reaction time: 0.25 h
Yield: 100.7 %

Procedure:
19.9 g Dichloromethyl methyl ether and 45.7 g tin chloride were dissolved in 70 mL dichloromethane. The solution was cooled to +5° C. and 20.0 g fluoronaphthalene in dichloromethane (49 mL) was added over a 60 min period, while keeping the temperature at 5° C. The reaction was brought to room temperature after the addition. After 4 h the reaction was quenched by slowly pouring it into an ice/water mixture. This mixture was stirred for 15 min and left standing overnight. The dichloromethane layer was washed with water, dried (sodium sulfate), filtered through celite and concentrated in vacuo to obtain 24.0 g of 4-fluoro-naphthalene-1-carbaldehyde as an off white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:11])[CH2:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].[CH2:12](O)[CH2:13][OH:14].C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([O:4][CH2:5][C:6]1([CH2:7][CH2:8][CH:9]=[CH2:10])[O:14][CH2:13][CH2:12][O:11]1)(=[O:3])[CH3:2]
Reactant: OCCO
Reactant: C=CCCC(=O)COC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=CCCC1(COC(C)=O)OCCO1
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 15.6 g. (0.1 mole) of 1-acetoxy-5-hexen-2-one, 18.6 g. (0.3 mole) of ethylene glycol in 250 ml. of benzene containing 1.56 g. of p-toluene sulfonic acid monohydrate is heated to reflux using a Dean-Stark water separator. After 2 hours, the reaction mixture is shaken well with 250 ml. of cold water. The aqueous layer is washed with 3×25 ml. of ether. The combined organic layers are dried over anhydrous magnesium sulfate. Evaporation of the solvent gives 2-acetoxymethyl-2-(3-buten-1-yl)-1,3-dioxolane in 90% yield as a light brown oil.