Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].C(O)C.Cl>O>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][N:21]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ncc(C(=O)OCC)cn2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ncc(C(=O)O)cn2)cc1

Procedure:
An eggplant type flask was charged with 2.6 g of the above Compound E, 0.8 g of potassium hydroxide, 45 ml of ethanol and 5 ml of water. The system was refluxed for one hour, and the resultant reaction liquid was poured into 100 ml of water, which was made acidic with hydrochloric acid and extracted with chloroform. The extract was dried over sodium sulfate, removed the solvent by distillation, and recrystallized with 50 ml of hexane. The crystalline product was recovered by filtration, and dried to provide 2.3 g of the object 2-(4-octyloxyphenyl)pyrimidine-5-carboxylic acid, which was the object product.
Reaction SMILES: C([O:8][C:9](=[O:33])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:32])[CH:16]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:17][S:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:19])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[CH2:21]([S:18]([NH:17][CH:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:33])=[O:8])=[O:32])[CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:20])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)CC(NS(=O)(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(NS(=O)(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 103 %

Procedure:
N-benzylsulfonyl-D,L-leucyl-L-proline benzyl ester (1.2 g) was dissolved in methanol (20 ml), and 10% palladium-carbon (120 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a white foam-like solid (1 g, 99%), which was directly used for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=O)[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.F[B-](F)(F)F.C([O+]([CH2:32][CH3:33])CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[N:8][C:9]3[C:10]=2[O:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[N:14]([CH3:17])[C:15]=3[N:8]2[CH2:33][CH2:32][CH2:4][CH2:5][CH2:6]2)[CH:7]=1
Reactant: CC[O+](CC)CC
Reactant: CN1C(=O)c2[nH]c3cc(Cl)ccc3c2Oc2ccccc21
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CN1C(N2CCCCC2)=C2N=c3cc(Cl)ccc3=C2Oc2ccccc21
Reaction time: 48 h

Procedure:
A solution of 5.0g of 3-chloro-7-methyl-7H-indolo[3,2-b][1,5]benzoxazepine-6(5H)-one in 60ml of methylene chloride was cooled to 15° and treated with 30ml of a 1N solution of triethyloxonium fluoroborate in methylene chloride. The mixture was stirred for 48 hrs. at ambient temperature. The precipitated solid was filtered, washed with methylene chloride and added to 10ml of piperidine, and the clear solution was heated for 8 hrs. on the steam bath. The mixture was diluted with water, and the precipitated solid was filtered and recrystallized from ethylacetate, mp. 244°-5°.
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[O:23])[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].Cl[CH2:38][C:39]1[CH:44]=[CH:43][N+:42]([O-:45])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]([O:36][CH2:38][C:39]5[CH:44]=[CH:43][N+:42]([O-:45])=[CH:41][CH:40]=5)=[CH:34][CH:35]=4)[CH2:28][CH2:29]3)=[O:23])[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(O)cc4)CC3)n2)cc1OC
Reactant: [O-][n+]1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(OCc5cc[n+]([O-])cc5)cc4)CC3)n2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
To a DMF (10 ml) solution of 1.50 g of 4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenol were added 1.00 g of 4-chloromethylpyridine-N-oxide and 3.00 g of cesium carbonate, followed by 30 minutes of stirring at room temperature. After warmed to 60° C., the mixture was further stirred for 30 minutes. Then, 1.00 g of 4-chloromethylpyridine-N-oxide and 1.50 g of cesium carbonate were added thereto and the whole was stirred at 60° C. for 1 hour. After cooling to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) and then recrystallization was carried out from ethanol to obtain 440 mg of 1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-[4-(1-oxido-4-pyridylmethoxy)phenyl]piperazine as pale yellow crystals.
Reaction SMILES: C1C(OC2C(I)=CC(C[C@H](N)C(O)=O)=CC=2I)=CC(I)=C(O)C=1.[CH:24]1[C:25]([CH2:42][C@H:43]([NH2:47])[C:44]([O-:46])=[O:45])=[CH:26][C:27]([I:41])=[C:28]([O:31][C:32]2[CH:33]=[C:34]([I:40])[C:35]([OH:39])=[C:36]([I:38])[CH:37]=2)[C:29]=1[I:30].O.[Na+].C(O)[C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH:26]1[C:25]([CH2:42][C@H:43]([NH2:47])[C:44]([OH:46])=[O:45])=[CH:24][C:29]([I:30])=[C:28]([O:31][C:32]2[CH:37]=[C:36]([I:38])[C:35]([OH:39])=[C:34]([I:40])[CH:33]=2)[C:27]=1[I:41]
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)[O-]
Agent: N[C@@H](Cc1cc(I)c(Oc2ccc(O)c(I)c2)c(I)c1)C(=O)O
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Solvent: O
Product: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O

Procedure:
FIG. 2 depicts graphs of liothyronine (T3) impurity over time at 40° C. for compositions containing 100 μg (“mcg”), 200 μg or 500 μg levothyroxine sodium (L), and either 3 mg or 10 mg mannitol (M). FIG. 3 depicts graphs of T3 impurity over time at 25° C. for compositions containing 100 μg, 200 μg or 500 μg levothyroxine sodium, and either 3 mg or 10 mg mannitol. The graphs in FIGS. 2 and 3 for the compositions containing 3 mg mannitol (open symbols) correspond to the results listed in Table 2. The graphs in FIGS. 2 and 3 for the compositions containing 10 mg mannitol (closed symbols) correspond to results of an analysis of the stability of levothyroxine in solid compositions containing 100 μg, 200 μg or 500 μg levothyroxine sodium and 10 mg mannitol. These solid compositions were formed by combining water, the levothyroxine sodium, the mannitol, and 500 μg dibasic sodium phosphate to form liquid mixtures, and then adding sodium hydroxide to provide a pH of about 11.8. Water for injection (USP) was added to each liquid mixture as needed to provide total volumes of 1 mL. The liquid mixtures were lyophilized to provide solid compositions, which were then stored in vials at temperatures of 25° C. or 40° C. The stability of the levothyroxine in the solid compositions over time at different temperatures was determined by measuring the amount of T3, as described above. The results of these measurements for the compositions containing 10 mg mannitol are listed in Table 3, below.
Reaction SMILES: [C:1]([N:5]([C:19]([C:21]1[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=[O:20])[NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([C:14](OC)=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>CCOCC.C(Cl)Cl>[C:1]([N:5]([C:19]([C:21]1[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=[O:20])[NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:31][CH2:30][C:29]([CH3:33])([CH3:32])[N:28]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)NN(C(=O)c2cccc(C)c2)C(C)(C)C)cc1
Reactant: CC(C)(N)CO
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cccc(C(=O)N(NC(=O)c2ccc(C3=NC(C)(C)CO3)cc2)C(C)(C)C)c1

Procedure:
1.2 g of N'-t-butyl-N-(4-carbomethoxybenzoyl)-N'-(3-toluoyl)hydrazine was heated in 2 ml of 2-amino-2-methyl-1-propanol at 90-100° C. for 5 hours. After cooling, the mixture was diluted with ether/methylene chloride and washed with 0.1 N HCl. The organic layer was evaporated to afford 1.0 g of the corresponding amide.
Reaction SMILES: [C:1]1([C:9]([O-:11])=[O:10])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.Cl[C:45]([O:47][CH2:48][CH3:49])=[O:46]>C1COCC1>[C:4]([C:1]1([C:9]([O:11][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[O:10])[CH:2]=[CH:3]1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C1(C(=O)[O-])C=C1
Reactant: CCOC(=O)Cl
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)OC(=O)C1(C(=O)OCC)C=C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 250 milliliter round-bottom flask was equipped with a magnetic stirrer and an addition funnel with N2 inlet. The flask was charged with 1.30 grams (0.008 mole) of monoethyl cyclopropene-1,1-dicarboxylate, 50 millilaters of dry THF, 2.3 grams (0.02 mole) of potassium carbonate (anhydrous), and 450 milligrams of dicyclohexano-18-crown-6 ether. The stirred reaction mixture was cooled to 0° C., and 0.90 gram (0.008 mole) of ethyl chloroformate in 10 millilaters of THF was added dropwise. The mixture was stirred for 21/2 hours at O° C. At this time an aliquot from the reaction mixture showed a very strong anhydride carbonyl stretch at 1820 cm-1 in the infrared indicating the formation of the mixed anhydride 1-carboethoxy-1-ethoxycarbonyloxycarbonyl-2-cyclopropene. The balance of the reaction mixture containing the mixed anhydride was carried on to Part E.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[S:6].Br[CH:12]([C:18](OCC)=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[S:6][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([OH:19])[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: NC(=S)c1cccc(Cl)c1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cccc(Cl)c2)nc1O
Temperature: 60 °C
Yield: 72.6 %

Procedure:
340 mg of 3-chlorothiobenzamide was dissolved in 10 ml of ethanol, 570 mg of diethyl bromomalonate was added to the solution, and the mixture was heated at 60° C. for 2 hours. After the reaction mixture was cooled, and the resulting crystal was collected by filtration and recrystallized from ethanol to give 408 mg of ethyl 2-(3-chlorophenyl)-4-hydroxy-5-thiazolecarboxylate. This product was hydrolyzed by a conventional process to give 306 mg of 2-(3-chlorophenyl)-4-hydroxy-5-thiazolecarboxylic acid (yield: 60%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25])=[N:15][C:16]#[N:17])C=C.[BH4-].[Na+].CO.C(Cl)(Cl)Cl>C1COCC1>[OH:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25])=[N:15][C:16]#[N:17]
Reactant: C=CCOc1cc(C#N)ccc1NC(=NC#N)Nc1ccccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: N#CN=C(Nc1ccc(C#N)cc1O)Nc1ccccc1Br
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a mixture of N-(2-Allyloxy-4-cyanophenyl)-N′-(2-bromophenyl)-N″-cyanoguanidine (100 mg, 0.25 mmol) and sodium borohydride (20 mg, 0.52 mmol) in THF (3 ml) was added at rt tetrakistriphenylphosphine palladium[0] (21 mg, 7 mol %). The reaction was stirred at rt until tlc showed no starting material present. The mixture was partitioned between ethyl acetate and 0.5 M sodium dihydrogen phosphate. After drying over MgSO4 filtration and evaporation under reduced pressure afforded a crude tan solid (100 mg). Column chromatography on silica gel eluting with 5% methanol/chloroform gave the title compound as a pale yellow solid (64 mg) which was recrystallized from chloroform (42 mg, 47%). 1H NMR(400 MHz,DMSO) δ 10.93 (s, 1H), 9.57 (s, 1H), 8.74(s, 1H), 7.84 (d, J=8.3 Hz, 1H),7.71 (d, J=7.8 Hz, 2H), 7-50-7.42 (m, 2H), 7-30-7.26 (m, 2H 7.17 (s, 1H), 7.08 (t, 1H); IR(KBr) 2224,2193 cm−1; MS(ES−) m/e 354,356 [M−H]−; MS(ES+) m/e 356,358 [M+H]+; mp. 175-176°.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:38]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:38])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OC(C)c1ccccc1F
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example A7, 10.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-[1-(2-fluorophenyl)ethoxy]thiophene-2-carboxylate and 950 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: CN[C@@H](CC1C=[C:13](O)[C:11]([OH:12])=[CH:10]C=1)C(O)=O.C(OC(Cl)C)(=O)C(C)(C)C.CN(C)C(=O)N(C)C.[P:34](=[O:38])([OH:37])([OH:36])[OH:35]>C1(C)C=CC=CC=1>[CH:11]([O-:12])([CH3:13])[CH3:10].[P:34](=[O:35])([OH:38])([OH:37])[OH:36]
Reactant: CN[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: CC(Cl)OC(=O)C(C)(C)C
Agent: O=P(O)(O)O
Solvent: CN(C)C(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC(C)[O-]
Temperature: 70 °C
Reaction time: 16 h

Procedure:
In an operation carried out in a manner similar to that described in Example 1, 42.3 grams (0.2 mole) of methyldopa, 40.3 milliliters (0.24 mole) of 1-chloroethyl pivalate, 14 grams of 4A molecular sieve pellets (1/16") and 85 milliliters of tetramethylurea are mixed together and heated in an atmosphere of nitrogen to 70° C. and maintained at this temperature for about 30 hours. During this time, the methyldopa dissolves with the formation of (R,S)-1-pivaloyloxyethyl ester product. Thereafter, the reaction mixture is cooled to 25° C. and diluted with 380 milliliters of toluene. The mixture is then washed with three 500 milliliter portions of saturated sodium bicarbonate solution and filtered to clarify the solution. To this solution is added 300 milliliters of isopropanol followed by 16.6 grams (0.14 mole) of 85 percent phosphoric acid and 0.100 gram of methyldopa (R,S)-POE ester phosphoric acid monoisopropanolate seed whereupon the product crystallizes. The crystal-containing slurry is aged for 16 hours at 20°-25° C., then filtered and washed with two 75 milliliter portions of isopropanol and dried in vacuo to obtain (R,S)-1-pivaloyloxyethyl (S)-3-(3,4-dihydroxyphenyl)-2-methylalaninate, phosphoric acid, monoisopropanolate salt.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[Li].C1(C)C=CC=CC=1.O>O1CCCC1>[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]([C:20]2[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=2[CH3:18])=[NH:13])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: [Li]c1c(C)cc(C)cc1C
Reactant: CC1=C(C)C(c2ccccc2C#N)C(C)=C1C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(C)C(c2ccccc2C(=N)c2c(C)cc(C)cc2C)C(C)=C1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 108.1 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzonitrile (6.3 mmol) in tetrahydrofuran (25.5 mL) was added dropwise a solution of 2,4,6-trimethylphenyllithium (12.5 mmol) in tetrahydrofuran (55.6 mL) at −78° C. under a nitrogen atmosphere. The temperature of the mixture was raised to room temperature and the mixture was stirred for 5 hrs. To the reaction mixture solution were added toluene and water to separate an organic layer and an aqueous layer. The organic layer was dried and the solvent was distilled off to give 2-(2,3,4,5-tetramethylcyclopentadienyl)-α-(2,4,6-trimethylphenyl) -benzenemethanimine (2.34 g) as a brown oily substance.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:57][S:58]([N:61]1[CH2:66][CH2:65][N:64]([CH2:67][CH2:68][CH2:69]O)[CH2:63][CH2:62]1)(=[O:60])=[O:59]>CN(C=O)C.C(Cl)Cl>[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:36][CH2:69][CH2:68][CH2:67][N:64]4[CH2:65][CH2:66][N:61]([S:58]([CH3:57])(=[O:60])=[O:59])[CH2:62][CH2:63]4)=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Reactant: CS(=O)(=O)N1CCN(CCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
Under nitrogen, diethyl azodicarboxylate (0.19 ml, 1.2 mmol) was added dropwise to a suspension of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), triphenylphosphine (0.31 g, 1.2 mmol) and 3-(4-methylsulfonylpiperazin-1-yl)propan-1-ol (0.2 g, 0.9 mmol) in DMF (4 ml). The mixture was stirred for 2 hours at ambient temperature. Methylene chloride was added and the mixture was poured onto silica and eluted with ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/4) followed by methanol/methylene chloride (1/9). The fractions containing the expected product were combined and evaporated. The residue was triturated with diethyl ether and filtered. The solid was washed with ether and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yl)oxy-6-methoxy-7-(3-(4-methylsulfonylpiperazin-1-yl)propoxy)cinnoline (90 mg, 28%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][S:4](=[O:9])(=[O:8])[N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[N:24]1[CH2:29][CH2:28][CH:27]([CH2:30]I)[CH2:26][CH2:25]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][S:4]2(=[O:9])=[O:8])[CH2:26][CH2:25]1
Reactant: COc1cc2ncnc(N3CCC(CI)CC3)c2cc1OC
Reactant: CC1=NS(=O)(=O)NC=C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1cc2ncnc(N3CCC(CN4C=CC(C)=NS4(=O)=O)CC3)c2cc1OC

Procedure:
A mixture of 3-methyl-6H-1,2,6-thiadiazine-1,1-dioxide (0.584 g) and 1-(6,7-dimethoxyquinazolin-4-yl)-4-iodomethylpiperidine (0.826 g) were heated under reflux with tetrabutylammonium fluoride (4 ml; 1.0M in tetrahydrofuran [T.H.F.]) for 24 hours. The solvent was then removed in vacuo and the residue was chromatographed on silica (Merck 60.9385) eluting with chloroform to give a foam. Crystallisation from ethyl acetate gave 1-(6,7-dimethoxyquinazolin-4-yl)-4-(1,1-dioxo-5-methyl-1,2,6-thiadiazin-2-yl)methylpiperidine as white needles, m.p. 203°-207°, (0.35 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:9])([CH2:7]O)[CH2:5][OH:6].[CH3:10][O:11][CH2:12][CH:13]=[O:14].C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[CH3:10][O:11][CH2:12][CH:13]1[O:6][CH2:5][C:4]([CH2:3][O:2][CH3:1])([CH3:9])[CH2:7][O:14]1
Reactant: COCC=O
Reactant: COCC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COCC1OCC(C)(COC)CO1
Yield: 91 %

Procedure:
A mixture of 670 g (5 moles) of 2-methoxymethyl2-methyl-1,3-propanediol, 479 g (5.5 moles) of 85% strength methoxyacetaldehyde and 250 ml of chloroform was heated with 10 g of pyridinium p-toluenesulfonate under a water separator until water no longer separated off. The solution was deionized using a mixed-bed ion exchanger, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 864 g (91% yield) of 2,5-dimethoxymethyl-5-methyl-1,3-dioxane of boiling point 95° C./10 mbar were obtained.
Reaction SMILES: [Br:1][CH:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][NH2:9])[O:3]1.[N+:10]([C:13]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:21][C:14]=1[O:15][CH:16]([CH3:20])[C:17](Cl)=[O:18])([O-:12])=[O:11]>C(Cl)Cl>[Br:1][CH:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][NH:9][C:17](=[O:18])[CH:16]([O:15][C:14]2[CH:21]=[C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH:23]=[CH:24][C:13]=2[N+:10]([O-:12])=[O:11])[CH3:20])[O:3]1
Reactant: NCC1OCCC(Br)O1
Reactant: CC(Oc1cc(Oc2ccc(F)cc2)ccc1[N+](=O)[O-])C(=O)Cl
Solvent: ClCCl
Product: CC(Oc1cc(Oc2ccc(F)cc2)ccc1[N+](=O)[O-])C(=O)NCC1OCCC(Br)O1
Temperature: -15 °C

Procedure:
N-(4-Bromo-1,3-dioxan-2-ylmethyl)amine (0.015 mole) triethylamine (5 ml) and methylene chloride (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The reaction mixture is cooled to about -15° C. and a solution of 2-[2-nitro-5-(4-fluorophenoxy)phenoxy]propionyl chloride (0.01 mole) in methylene chloride (50 ml) is added dropwise with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature with continued stirring. After this time the mixture is transferred to a separatory funnel and is washed with water and dilute aqueous sodium bicarbonate. The washed solution is then dried, filtered and stripped of solvent leaving a residue. The residue is then recrystallized from a toluene/hexane mixture to yield the desired product N-(4-bromo-1,3-dioxan-2-ylmethyl)-2-[2-nitro-5-(4-fluorophenoxy)phenoxy]propionamide.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH2:20][CH2:21][CH2:22]Cl)(=[O:19])=[O:18])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(#N)C>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:22][CH2:21][CH2:20][S:17]2(=[O:19])=[O:18])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(NS(=O)(=O)CCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCCS2(=O)=O)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
13.0 g (40.0 mmol) of caesium carbonate are added to a solution of 7.40 g (26.6 mmol) of N-(4-nitrophenyl)-3-chloropropane-1-sulfonamide in 150 ml of acetonitrile, and the mixture is stirred at 70° C. for 18 hours. The reaction mixture is subjected to conventional work-up, and the crude product is chromatographed on a silica-gel column using ethyl acetate/petroleum ether as eluent, giving 2-(4-nitrophenyl)isothiazolidine 1,1-dioxide as a yellowish solid; ESI 243.