Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:7]([C:13]([O:15]CC)=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+]>C(O)C>[CH2:11]([O:10][C:8]([CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:13]([OH:15])=[O:14])=[O:9])[CH3:12]
Reactant: CCCCCCC(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C(=O)O)C(=O)OCC
Reaction time: 2 h

Procedure:
To a solution of diethyl 2-hexylmalonate of Example 8 (244.36 g, 1.000 mol) in 25 mL of absolute ethanol in a 2-L, 3-necked Morton flask was added a solution of potassium hydroxide (59.9 g, 0.907 mol)(weight adjusted for 85% assay of commercial potassium hydroxide) in 450 mL of absolute ethanol dropwise via a 500-mL pressure-equalizing dropping funnel over 75 min. The funnel was washed with 25 mL of absolute ethanol. The reaction mixture was stirred for 2 h, and 300 mL of ethanol was then removed under reduced pressure. Water (500 mL) was added, and the mixture extracted with 500 mL of heptane to remove unreacted diethyl 2-hexylmalonate. The aqueous solution was acidified with 12 M HCl to pH 2 then extracted with 500 mL of heptane. The heptane solution was dried (MgSO4) and the solvent removed under reduced pressure to give 2-(ethoxycarbonyl)octanoic acid as a colorless oil. Traces of ethanol were removed by adding 20 mL of toluene to the crude product, followed by stripping of the solvent at 1 mm Hg of pressure with stirring. The yield was 190.9 g (0.8827 mol, 88.3% based on diethyl 2-hexylmalonate, 97% based on potassium hydroxide).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]([C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8])=[O:5])[CH3:2].[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)CC1>>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[C:25]([CH3:35])=[CH:24][C:23]([CH3:20])=[CH:28][N:27]=3)[CH2:30][CH2:31]2)=[O:16])=[CH:18][CH:19]=1)([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)NC(C)(C)c1ccc(C(=O)OC)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: CCOC(=O)NC(C)(C)c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Yield: 84.4 %

Procedure:
Using methyl 4-(1-ethoxycarbonylamino-1-methylethyl)benzoate (174 mg) described in Preparation Example 70 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (157 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (235 mg) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[C:36]([N:41]=[C:42]=[S:43])(=[O:40])[O:37][CH2:38][CH3:39]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([NH:28][C:42]([NH:41][C:36](=[O:40])[O:37][CH2:38][CH3:39])=[S:43])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(COc2ccc(CNc3ncc(I)cc3N)cc2OC)cc1
Reactant: CCOC(=O)N=C=S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(=S)Nc1cc(I)cnc1NCc1ccc(OCc2ccc(OC)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
To a stirred solution of 5-iodo-N2-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyridine-2,3-diamine (Example 3-16-2) (2.00 g, 4.07 mmol) and triethylamine (1.30 g, 1.8 mL, 12.85 mmol) in tetrahydrofuran (20 mL) was added O-ethyl carbonisothiocyanatidate (1.07 g, 8.20 mmol). The reaction mixture was allowed to stir at room temperature. After 3 h, the mixture was filtered, and the filtrate was concentrated to provide 2.30 g of ethyl N-({5-iodo-2-[({3-methoxy-4-[(4-methoxyphenyl)methoxy]phenyl}methyl)amino]pyridin-3-yl}carbamothioyl)carbamate as a yellow oil.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:19].[C:25](Cl)(=[O:31])[CH2:26][CH2:27][C:28](Cl)=[O:29]>CN(C)C=O>[NH3:1].[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH:14][C:25](=[O:31])[CH2:26][CH2:27][C:28]([NH:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][CH:6]=[C:19]([CH2:18][N:20]3[CH2:23][CH2:24][CH2:22][CH2:21]3)[CH:15]=2)=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCCCOc1cccc(CN2CCCC2)c1
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: N
Product: O=C(CCC(=O)NCCCOc1cccc(CN2CCCC2)c1)NCCCOc1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-[3-(1-pyrrolidinylmethyl)phenoxy]propylamine (0.7 g) and triethylamine (0.4 g) dissolved in dry dimethylformamide (5 ml) is added in dropwise fashion succinyl chloride (0.17 ml) at -10° C., and then the reaction mixture is slowly warmed up to room temperature, and stirred for 4 hours. The solvent is removed under reduced pressure, and the residue is distributed to ethyl acetate and saturated sodium hydrogencarbonate solution, and the organic layer is separated, dried on anhydrous sodium, sulfate and evaporated. The residue is chromatographed on a column of silica gel, the fractions eluted with methanol are removed, and the fractions eluted with methanol-conc. aqueous ammonia (50:1 (V/V)) solution give the titled compound (0.55 g) as an oily material. The oily material thus obtained is dissolved in ethanol, and a solution of oxalic acid (0.2 g) in ethanol is added. White crystals precipitated are collected by filtration and further recrystallized from an aqueous ethanol to give the oxalate of the titled compound. mp 157°-159° C.
Reaction SMILES: [BrH:1].C(OC([NH:12][CH:13]([C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)[C:14]([O:16][CH3:17])=[O:15])=O)C1C=CC=CC=1.CCOCC>C(O)(=O)C>[BrH:1].[NH2:12][CH:13]([C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)c1ccco1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C(N)c1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To magnetically stirred 33 wt % hydrogen bromide (2.00 ml, 11.04 mmol) in acetic acid was added methyl 2-(((benzyloxy)carbonyl)amino)-2-(furan-2-yl)acetate (579 mg, 2 mmol). After stirring at room temperature for 1 hr, 25 mL of anhydrous ether was added to give methyl 2-amino-2-(furan-2-yl)acetate hydrobromide (468 mg, 1.983 mmol, 99% yield) as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 2H), 7.81 (dd, J=1.8, 0.8 Hz, 1H), 6.69 (m, 1H), 6.57 (dd, J=3.3, 1.9 Hz, 1H), 5.61 (s, 1H), 3.78 (s, 3H).
Reaction SMILES: [CH:1]1([C:10]([OH:12])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:13][N:14]([CH3:31])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1>>[CH3:13][N:14]([CH3:31])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=2)[C:10]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:12])=[CH:19][CH:20]=1
Reactant: O=C(O)C1CCc2ccccc21
Reactant: CCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCc3ccccc32)cc1
Yield: 16 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using indan-1-carboxylic acid (0.46 g) and [(4-dimethylaminophenyl)methyl](4-ethylphenyl)amine (0.6 g) as starting materials, N-[(4-dimethylaminophenyl) methyl]-N-(4-ethylphenyl)indan-1-carboxamide (0.15 g) was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)[C:5](=[O:21])[O:6][CH2:7][C@@:8]([OH:20])([CH3:19])[CH2:9][N:10]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[C:11]1Cl>CN(C=O)C>[CH3:3][N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)[C:5](=[O:21])[O:6][CH2:7][C@:8]1([CH3:19])[O:20][C:11]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:10]2[CH2:9]1
Reactant: CN(Cc1ccc(OC(F)(F)F)cc1)C(=O)OC[C@](C)(O)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(OC(F)(F)F)cc1)C(=O)OC[C@@]1(C)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
Sodium hydride (0.28 g, 7.04 mmol) was added to a solution of (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl N-methyl-N-(4-trifluoromethoxybenzyl)carbamate prepared in Example 72 (2.74 g, 5.87 mmol) in DMF (20 ml) followed by stirring for 1 hour with cooling on ice-bath. To the reaction mixture, ice-water was added, and the precipitates were filtered off, washed with water and then recrystallized from isopropanol to afford (R)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl N-methyl-N-(4-trifluoromethoxybenzyl)carbamate (1.40 g, yield 55%) as a white solid.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:15][N:13]([CH:12]=[C:7]([C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[C:8]#[N:9])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)C(=O)CC#N
Product: CN(C)C=C(C#N)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 25.0 g of pivaloyl acetonitrile in 50 ml of N,N-dimethylformamide dimethyl acetal was stirred at room temperature for 8 hours under argon and then the solvent was evaporated and n-hexane was added with stirring. The product was collected by filtration to give 34.6 g of 2-[(dimethylamino)methylene]-4,4-dimethyl-3-oxopentanenitrile.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-:32].[Na+].Cl>CC(C)=O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([OH:4])=[O:32])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: [OH-]
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Reaction time: 20 h

Procedure:
To a stirred solution of 2,2,2-trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone (0.20 mmol) in acetone (1.2 mL) was added 0.15 mL of 2.5 N sodium hydroxide. After stirring for 20 hours the mixture was acidified with 2.0 N hydrochloric acid, extracted into ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. The solution was then evaporated and the residue purified by trituration with diethylether. The solid (0.066 g, 83%) was collected and dried, m.p. 168° C. MS [(+)ESI, m/z]: 395 [M+H]+ Anal. Calcd for C21H17CIN2O4: C, 63.56; H, 4.32; N, 7.06. Found: C, 63.66; H, 4.48; N, 6.86
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH3:7][CH:8]1[CH2:13][NH:12][CH:11]([CH3:14])[CH2:10][NH:9]1>C1(C)C=CC=CC=1>[Cl:1][CH:2]([Cl:6])[C:3]([N:9]1[CH2:10][CH:11]([CH3:14])[N:12]([C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])[CH2:13][CH:8]1[CH3:7])=[O:4]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC1CNC(C)CN1
Solvent: Cc1ccccc1
Product: CC1CN(C(=O)C(Cl)Cl)C(C)CN1C(=O)C(Cl)Cl
Yield: 23.8 %

Procedure:
29.4 g (0.2 mol) of dichloroacetyl chloride were added dropwise to a solution of 22.8 g (0.2 mol) of 2,5-dimethyl-piperazine in 150 ml of toluene at 20° C., while stirring. The mixture was subsequently stirred at 20° C. for 5 hours. Thereafter, the precipitate which had formed was filtered off and recrystallized twice from toluene. 8 g (24% of theory) of N,N'-bis-(dichloroacetyl)-2,5-dimethyl-piperazine were obtained in this manner in the form of colorless crystals of melting point 215° C.
Reaction SMILES: [CH:1]([O:3][CH:4]1CC[CH2:7][N:6]([C:10]2[N:11]=[C:12]3[CH:22]=[C:21]([CH2:23][CH2:24][C:25]4[S:26][CH:27]=[C:28]([CH:30]5[CH2:33]CC5)[N:29]=4)[CH:20]=[CH:19][N:13]3[C:14](=[O:18])[C:15]=2[CH:16]=[O:17])[CH2:5]1)=O.C(C1N=C(CCC2C=CN3C(=O)C=C(N4CCOCC4)N=C3C=2)SC=1)C>>[CH2:30]([C:28]1[N:29]=[C:25]([CH2:24][CH2:23][C:21]2[CH:20]=[CH:19][N:13]3[C:14](=[O:18])[C:15]([CH:16]=[O:17])=[C:10]([N:6]4[CH2:7][CH2:1][O:3][CH2:4][CH2:5]4)[N:11]=[C:12]3[CH:22]=2)[S:26][CH:27]=1)[CH3:33]
Reactant: O=COC1CCCN(c2nc3cc(CCc4nc(C5CCC5)cs4)ccn3c(=O)c2C=O)C1
Agent: CCc1csc(CCc2ccn3c(=O)cc(N4CCOCC4)nc3c2)n1
Product: CCc1csc(CCc2ccn3c(=O)c(C=O)c(N4CCOCC4)nc3c2)n1
Yield: 90 %

Procedure:
Reactions were performed in the same manner as in Example 1, (I) by using 8-[2-(4-ethyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (120 mg, 0.324 mmol) to obtain 116 mg (90%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)([CH2:12][CH2:13][O:14][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:8]1)=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2(CCO)CCN(C(=O)c3cc(-n4cnnn4)ccc3OC)C2)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CCOS(C)(=O)=O)CCN(C(=O)c3cc(-n4cnnn4)ccc3OC)C2)cc1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (0.43 g, 0.97 mmol), triethylamine (3.3 mL, 2.4 mmol), and anhydrous dichloromethane (30 mL). Cool the reaction mixture to -5° C. with an salt-ice bath. Slowly, add methanesulfonyl chloride (0.082 mL, 1.06 mmol) at such a rate that the temperature of the reaction mixture does not rise above 2° C. Warm to ambient temperature. After 18 hours, quench the reaction by the addition of ice. Separate the organic layer and extract 3 times with 1M hydrochloric acid solution and 2 times with a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and concentrate invacuo to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC)=[O:17].Cl.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:23]([CH3:24])[CH2:22][C:26]([OH:25])=[O:17])=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2ccccc2)c(F)c1
Reactant: CCOC(=O)Cl
Reactant: C1CCOC1
Agent: Cl
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Grignard solution, prepared from 3.11 g. of 4-(1-bromo-2-propyl)-2-propyl)-2',4'-difluorobiphenyl, in 40 ml. of THF is added slowly to a solution of 1.2 g. of ethyl chloroformate in 20 ml. of THF. 15 ml. of concentrated hydrochloric acid are added. The mixture is heated under reflux for 24 hours and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][CH2:11][OH:12])[C:3]=1[N+:13]([O-:15])=[O:14].[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1.[NH4+].[Cl-]>C(Cl)Cl>[C:16]([Si:20]([CH3:22])([CH3:21])[O:12][CH2:11][CH2:10][O:9][C:4]1[C:3]([N+:13]([O-:15])=[O:14])=[C:2]([NH2:1])[CH:7]=[C:6]([Cl:8])[N:5]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cc(Cl)nc(OCCO)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-amino-6-chloro-3-nitro-pyridin-2-yloxy)-ethanol (4.40 g, 18.8 mmol, prepared as described in the previous step) and tert-butyl-chloro-dimethyl-silane (3.12 g, 20.7 mmol) in DCM (50 mL) was added imidazole (1.80 g, 26.4 mmol). After stirring at room temperature for 2 h, the resulting mixture was treated with saturated NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (3×50 mL), brine (50 mL), and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (0:100-20:80 EtOAc/hexane) to yield 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-6-chloro-3-nitro-pyridin-4-ylamine as a light yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 6.35 (s, 1H), 6.17 (br. s., 2H), 4.49 (t, J=5.1 Hz, 2H), 3.96 (t, J=5.1 Hz, 2H), 0.88 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: C1([N:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[P:8](=[O:11])([OH:10])[OH:9])C=CC=CC=1.C(N)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.[C:36]1([CH3:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:42]([N:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[P:8](=[O:9])([OH:10])[O:11][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NCc1ccccc1
Reactant: CCCCCCCCCN(c1ccccc1)P(=O)(O)O
Reactant: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCN(Cc1ccccc1)P(=O)(O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (±) phenyl nonyl phosphoryl chloride (Example C) (2.0 g, 6.3 mmol) in toluene (20 mL) at 0° C. is added a solution of benzylamine (0.67 g, 6.3 mmol) and triethylamine (1.3 mL, 9.4 mmol) in toluene (5 mL) over 5 minutes. The mixture is allowed to warm to room temperature and is stirred for 90 minutes. The mixture is filtered, and the filtrate concentrated. Flash chromatography (3:2 hexane/ethyl acetate) affords 2.1 g of the title compound as a colorless oil; 1H NMR (200 MHz, CDCl3)δ 7.40-7.10 (m, 10 H), 4.19 (dd, J=10 and 7 Hz, 2 H), 4.19-4.05 (m, 2 H), 3.20-3.00 (m, 1 H), 1.70-1.60 (m, 2 H), 1.35-1.20 (m, 12 H), 0.89 (t, J=7 Hz, 3 H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([NH:15][NH2:16])=[CH:11][C:10]=1[CH:17]1[CH2:19][CH2:18]1.[N:20]#[C:21]Br>>[Cl:8][C:9]1[C:10]([CH:17]2[CH2:19][CH2:18]2)=[CH:11][C:12]2[N:13]([C:21]([NH2:20])=[N:16][N:15]=2)[N:14]=1
Reactant: NNc1cc(C2CC2)c(Cl)nn1
Reactant: N#CBr
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc2cc(C3CC3)c(Cl)nn12

Procedure:
(6-Chloro-5-cyclopropylpyridazin-3-yl)hydrazine trifluoroacetic acid salt (W3.012; 400 mg) was converted and worked up analogously to W2.008, except that, instead of 0.5, one further equivalent of cyanogen bromide solution was added. 260 mg of the title compound were obtained in sufficient purity.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:14])=[CH:10][C:11]([OH:13])=O.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH3:40][C:41]1([CH2:47][CH2:48][C:49]2[C:54]([CH3:56])([CH3:55])[CH2:53][CH2:52][CH2:51][C:50]=2[CH3:57])[NH:46][CH2:45][CH2:44][CH2:43][O:42]1>C1COCC1.CN(C1C=CN=CC=1)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH3:14])=[CH:10][C:11]([N:46]1[CH2:45][CH2:44][CH2:43][O:42][C:41]1([CH3:40])[CH2:47][CH2:48][C:49]1[C:54]([CH3:56])([CH3:55])[CH2:53][CH2:52][CH2:51][C:50]=1[CH3:57])=[O:13]
Reactant: CC(=CC(=O)O)c1ccc(O)cc1O
Reactant: CC1=C(CCC2(C)NCCCO2)C(C)(C)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=CC(=O)N1CCCOC1(C)CCC1=C(C)CCCC1(C)C)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 11.1 g (0.050 mol) of 3-(2,4-dihydroxy-phenyl)-3-methyl-acrylic acid in 500 mL of anhydrous THF is added 10.3 g (0.050 mol) of DCC. After stirring for 10 min, 6.8 g (0.050 mol) of HOBt, 11.3 g (0.045 mol) of 2-methyl-2-[2-(2,6,6-trimethyl-cyclohex-1-enyl)-ethyl]-[1,3]oxazinane (8) and 1.1 g (0.009 mol) of DMAP are added and stirred at 0° C. for 1 h, warmed to room temperature and stirred for an additional 24 h. The mixture is cooled to 0° C., filtered and the solvent is removed in vacuo. The residue is diluted with ethyl acetate and washed three times with saturated sodium bicarbonate, followed by 10% citric acid and brine. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product 9 is further purified by flash chromatography on basic alumina with 20:1 chloroform/methanol.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([CH:7]1[CH2:11][O:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)=[N:8]1)=[O:6].C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:3][O:4][C:5]([C:7]1[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[O:10][CH:11]=1)=[O:6]
Reactant: COC(=O)C1COC(CCCCC2(C)OCCO2)=N1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1coc(CCCCC2(C)OCCO2)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (1.04 g, 3.83 mmol) in CH2Cl2 (30 mL) at 0° C. was treated with DBU (0.72 mL, 4.79 mmol). Then, bromotrichloromethane (0.95 mL, 9.58 mmol) was added dropwise over 20 min and the reaction mixture was stirred at 0° C. for 4 h then at rt overnight. Additional DBU (0.72 mL, 4.79 mmol) and bromotrichloromethane (0.95 mL, 9.58 mmol) were added at 0° C. and the reaction mixture stirred at rt for 24 h. Sat. aq. NaHCO3 was then added and the aq. phase was extracted with CH2Cl2 (3×). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1→1:1 hept-EA) gave the title compound as a white solid. TLC: rf (1000:50:4 CH2Cl2-MeOH—NH3)=0.25. LC-MS-conditions 02: tR=0.84 min [M+H]+=270.35.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])(=[O:5])=[O:4].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:21])=[O:10])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1cccc(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1

Procedure:
3-(N,N-Dimethylsulfamoyl)benzoic acid (200 mg, 0.872 mmol) was refluxed overnight in the presence of concentrated sulfuric acid (5.64 mg, 0.044 mmol) in methanol (10 mL) at 70° C. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography affording the title compound (125 mg). 1H NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.27 (d, 1H, J=8.0 Hz), 7.97 (d, 1H, J=7.2 Hz), 7.65 (t, 1H, J=8.0 Hz), 3.96 (s, 3H), 2.74 (s, 6H). ESI-MS: 244.0 [M+H]+.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3](=O)[O:2]1.[N+:12]([C:15]1[CH:16]=[C:17]([CH2:21]C(O)=O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C([O-])(=O)C.[Na+]>C(O)C>[N+:12]([C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH:21]=[C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[C:1](=[O:11])[O:2]1)([O-:14])=[O:13]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1OC(=Cc2cccc([N+](=O)[O-])c2)C2=C1CCCC2
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
4,5,6,7-Tetrahydro-isobenzofuran-1,3-dione (1) (2.50 g, 16.4 mmol) and 3-nitro phenyl acetic acid (2.72 g, 15.0 mmol) were heated in the presence of sodium acetate (60.0 mg, 0.750 mmol) to 240° C. using a ‘Wood's Alloy’ bath. Once the reaction had reached 240° C. an additional amount of sodium acetate (60.1 mg, 0.750 mmol) was added. The reaction mixture was then heated for a further 45 minutes and then cooled to 80° C. Ethanol (20 ml) was added to the thick gum and the mixture slurried for 30 minutes. The resulting suspension was cooled to ambient temperature and filtered. The solid was further washed with additional cold ethanol (2×5 ml) and dried to afford the desired product as a mixture of geometric isomers. Main peak in LC-MS, (2.48 g) and was taken through crude; m/z (LC-MS, ESP), RT=4.48 mins (no ionization observed).