Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([Cl:12])=[O:9]
Reactant: Cc1occc1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1occc1C(=O)Cl

Procedure:
A first reaction mixture of chloroacetaldehyde dimethylacetal (300 g), water (400 mL) and 36% hydrochloric acid (40 mL) was stirred and brought to reflux. When the first reaction mixture became homogenous, it was cooled and added to a stirred solution of ethyl acetoacetate (260 g) and pyridine (500 mL) and left stirring at ambient temperature for 72 hours, to produce a second reaction mixture. The organic layer was then separated from the second reaction mixture and the aqueous layer was diluted with water and then extracted with methylene chloride. The combined organics were washed with 2N hydrochloric acid, followed by removal of the solvent. The residue was treated with a solution of sodium hydroxide (80 g) in water (700 mL) and ethanol (100 mL), to produce a third reaction mixture. After refluxing for 1 hour the third reaction mixture was poured into ice/water and acidified with hydrochloric acid. A cream colored precipitate formed. This precipitate was collected on a filter, washed with water and dried to give 2-methyl-3-furancarboxylic acid, 180 g. 100 g of the 2-methyl-3-furancarboxylic acid was added in portions to thionyl chloride (500 mL) and refluxed for 3 hours. Excess thionyl chloride was then distilled off to produce a residue. The residue was distilled using a water pump, to give 2-methyl-3-furanylcarboxylic chloride, bp. 62° C., 100 g.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.S(Cl)([Cl:14])=O>>[F:1][C:2]1[C:3]([C:9]([Cl:14])=[O:11])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ncc(F)cc1F

Procedure:
A suspension of 5.00 g (31.4 mmol) of 3,5-difluoropyridine-2-carboxylic acid in thionyl chloride (21 ml) was heated to reflux for 5 h. The solution was concentrated, and the residue was twice taken up in a little toluene and concentrated again. This gave 3.80 g of a solid, which was converted further directly without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[CH2:19]Br)=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[OH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[CH2:19][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: O=c1c(-c2ccc(O)cc2)c(CBr)oc2cc(O)cc(O)c12
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(O)cc2)c(CN2CCCCC2)oc2cc(O)cc(O)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
4',5,7-Trihydroxy-2-bromomethylisoflavone (160 mg) was dissolved in 2 ml N,N-dimethylformamide, 100 mg piperidine was added to the solution, and the mixture was stirred at room temperature for three hours. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol=96:4), and the solid thus obtained was recrystallized from ethanol, giving 150 mg of 4',5,7-trihydroxy-2-piperidinomethylisoflavone.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:12]1C[O:15][CH2:14][CH2:13]1.BrCCCO>C(OCC)(=O)C>[OH:15][CH2:14][CH2:13][CH2:12][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCOC1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: CCOC(C)=O
Product: OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
Potassium carbonate (269 g) and pyrrolidine (200 mL) were added in that order to a THF solution (500 mL) of 3-bromopropanol (200 g) at 0° C. The reaction liquid was stirred at room temperature for 15 hours, then ethyl acetate (500 mL) was added to it, and further stirred at room temperature for 1 hour. The obtained reaction liquid was filtered through Celite, and the solid on the Celite was washed with ethyl acetate. The wash liquid and the filtrate were concentrated under reduced pressure, and ethyl acetate (500 mL) was added to the resulting residue, then stirred for 1 hour and filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified through distillation (boiling point: 62° C., 1 mmHg) to obtain (3-hydroxypropyl)pyrrolidine (156 g, yield 95%).
Reaction SMILES: [C:1]([C:3]1[C:4]([SH:11])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].[OH-].[K+].Cl[CH2:15][C:16]#[N:17]>CN(C=O)C>[NH2:2][C:1]1[C:3]2[C:4](=[N:5][C:6]([CH3:10])=[CH:7][C:8]=2[CH3:9])[S:11][C:15]=1[C:16]#[N:17]
Reactant: N#CCCl
Reactant: Cc1cc(C)c(C#N)c(S)n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(N)c(C#N)sc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
The 3-cyano-4,6-dimethyl-2-mercaptopyridine (500 mg, 3.04 mmol) was stirred in DMF (6.0 mL). An aqueous 10% KOH solution (1.71 mL, 3.04 mmol) was added, followed by chloroacetonitrile (0.19 mL, 3.04 mmol). The reaction was stirred at RT for 15 minutes, LC/MS indicates initial thio-alkylation is complete. A second equivalent of 10% KOH (1.71 mL, 3.04 mmol) was added and the resulting slurry was warmed to 50° C. and stirred about 30 min. LC/MS indicates reaction is done. The slurry was cooled to RT, then poured into 80 g of crushed ice and allowed to warm until the ice melted. The cold slurry was poured through filter paper, washing the solid with cold water. The solid was collected and dried in a vacuum oven to give 580 mg (94%) of the pure product as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.09 (s, 1H), 6.50 (s, 2H), 2.70 (s, 3H), 2.49 (s, 3H). LC/MS: RT=0.56 min., m/z=204.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:6]2[C:7]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([C@H:22]([NH:25]C(=O)OC(C)(C)C)[CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.Cl.C(O)(C)C.C([O-])(O)=O.[Na+]>C(OC(C)C)(=O)C>[NH2:25][C@H:22]([CH2:23][CH3:24])[C:20]([NH:19][C:16]1[CH:17]=[N:18][C:13]([O:12][C:7]2[C:6]3[C:2]([CH3:1])([CH3:33])[CH2:3][O:4][C:5]=3[C:10]([CH3:11])=[CH:9][CH:8]=2)=[CH:14][CH:15]=1)=[O:21]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)OC(C)C
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
The 1,1-dimethylethyl {(1R)-1-[({6-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)carbonyl]propyl}carbamate (Intermediate 30, 480 mg, 1.05 mmol) was dissolved in iso-propyl acetate (5 mL) and HCl 5-6N in isopropanol (1 ml, 5.25 mmol) was added. The solution was stirred at room temperature for 1 hour and then heated to −50-55° C. until complete conversion. The mixture was cooled to room temperature and treated with an aqueous saturated solution of NaHCO3. Two phases were separated and the organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol 95:5 as eluents affording the title compound (0.31 g) as yellowish foam.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7]1)=[O:5])C.[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH2:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C:6]([CH3:22])([C:4]([OH:3])=[O:5])[CH2:7]1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a −78° C. solution of the product of Example 45A (6.0 g, 20.6 mmoles) in THF (50 mL) was added a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 22.7 mmoles). After 35 min, iodomethane (1.4 mL, 22.7 mmoles) was added and the reaction was slowly warmed to room temperature and stirred overnight. The reaction was quenched with aqueous sat. ammonium chloride and extracted with Et2O. The organic layer was then rinsed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane→65:35 hexane:EtOAc). The resulting ester was hydrolyzed overnight at room temperature in THF (15 mL), H2O (10 mL), and EtOH (15 mL) with NaOH (2.5 g). The solution was concentrated under vacuum; the residue was dissolved in saturated ammonium chloride; and, the solution was extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried over sodium sulfate, filtered, and concentrated under vacuum to yield the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(O)c(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
3,4-Dihydroxybenzaldehyde (30.2 g, 219 mmol) is dissolved in DMF (300 mL) and added to a suspension of NaH (60% oil, 17.2 g, 430 mmol) in DMF (500 mL) at RT. The mixture is stirred for 30 minutes and benzyl chloride (17.3 mL, 150 mmol) is added at 0° C. The reaction is stirred overnight. The solvent is removed by evaporation and the residue is dissolved in water (500 mL). The mixture is extracted three times with CH2Cl2. The aqueous layer is acidified with HOAC (100 mL). The product is precipitated and filtered, washed with water to provide 3-benzyloxy-4-hydroxybenzaldehyde.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][O:33][CH2:32]1>>[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][O:33][CH2:32]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCCCC1CCCOC1
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 243 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: ClC1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[C:47]([F:64])=[C:48]([NH:52][S:53]([C:56]3[C:61]([F:62])=[CH:60][CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)=O)[CH:40]=[CH:39][N:38]=1.[CH:65]1([C:71](=[S:73])[NH2:72])[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]1>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:73][C:71]([CH:65]3[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]3)=[N:72][C:44]=2[C:46]2[C:47]([F:64])=[C:48]([NH:52][S:53]([C:56]3[C:61]([F:62])=[CH:60][CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)[CH:40]=[CH:39][N:38]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Reactant: NC(=S)C1CCCCC1
Agent: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCCCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Yield: 66 %

Procedure:
Following a procedure analogous to Intermediate 6 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.45 g, 1.019 mmol) and cyclohexanecarbothioamide (0.18 mg, 1.23 mmol) the title compound of Step B was obtained (0.38 g, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 7.61-7.75 (m, 1H), 7.39-7.50 (m, 2H), 7.32 (t, J=7.9 Hz, 1H), 7.24 (t, J=9.1 Hz, 2H), 6.86 (d, J=5.3 Hz, 1H), 2.96-3.12 (m, 1H), 2.09 (d, J=10.6 Hz, 2H), 1.78 (dd, J=9.7, 3.2 Hz, 2H), 1.68 (d, J=12.5 Hz, 1H), 1.47-1.61 (m, 2H), 1.33-1.45 (m, 2H), 1.21-1.32 (m, 1H). m/z (ES+): 566 [M+H]+.
Reaction SMILES: [NH3:1].[C:2]([O:6][CH3:7])(=[O:5])[CH:3]=[CH2:4]>>[CH3:7][O:6][C:2]([CH2:3][CH2:4][N:1]([CH2:4][CH2:3][C:2]([O:6][CH3:7])=[O:5])[CH2:4][CH2:3][C:2]([O:6][CH3:7])=[O:5])=[O:5]
Reactant: N
Reactant: C=CC(=O)OC
Product: COC(=O)CCN(CCC(=O)OC)CCC(=O)OC
Temperature: 0 °C
Yield: 76 %

Procedure:
While vigorously stirring at 0° C., 5.00 g of 28% aqueous ammonia was added to 21.2 g of methyl acrylate. The resulting mixture was heated gradually to 25° C. over 20 hours. After concentration under reduced pressure, the residue was purified by distillation under reduced pressure, whereby tris(2-methoxycarbonylethyl)amine was obtained (boiling point: 143° C./70 Pa, yield: 76%),
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[CH3:15][S:16][C:17]1[N:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][N:18]=1>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([CH:23]([C:21]2[CH:20]=[CH:19][N:18]=[C:17]([S:16][CH3:15])[N:22]=2)[OH:24])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CSc1nccc(C=O)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1nccc(C(O)c2cnc(Cl)nc2Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-bromo-2,4-dichloropyrimidine (14.83 g, 65 mmol) in THF (200 mL) was added isopropylmagnesium chloride (78 mL, 1M, 78 mmol) dropwise at −30° C. After 30 minutes, 2-(methylthio)pyrimidine-4-carbaldehyde (10 g, 65 mmol) was added to the mixture. The mixture was warmed to 0° C. and stirred for 1 hour. Then the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (200 mL). The filtrate was washed with water (3×25 mL), brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (silica, 20 g, 200-300 mesh, eluting with methanol:dichloromethane, 1:50) to afford (2,4-dichloro-pyrimidin-5-yl)-(2-methylsulfanyl-pyrimidin-4-yl)-methanol. (Yield 13.85 g, 71%).
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24].[OH-].[K+].C(O)C>C(O)C>[OH:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][NH:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCCOCCCl
Reactant: CCCCCCCCCCCCCCCCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNCCOCCO
Temperature: 25 °C
Yield: 70 %

Procedure:
Into a 1 l rounded-flask, were introduced 48.2 g of hexadecyl amine and 700 ml of ethanol. The mixture was heated to reflux, and then was gradually added 11 ml of 2-(2-chloroethoxy)ethanol. The mixture was refluxed for 3 hours and cooled to a room temperature. Thereto was added solution of KOH/ethanol to produce precipitates, which were removed by filtration. The filtrate was concentrated under reduced pressure, and then was recrystallized from ethanol, and dried to give 24.1 g of the title compound(Yield: 70%) as white powder, which was identified by IR and NMR. The results are shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O=[C:25]1[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:21][CH:25]4[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]4)=[CH:22][CH:23]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(N)cc3)n2)cc1Cl
Reactant: O=C1CC(C(=O)O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(NC4CC(C(=O)O)C4)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (250 mg, 0.531 mmol) in Methanol (1478 μl) at room temperature was added 3-oxocyclobutanecarboxylic acid (60.5 mg, 0.531 mmol) followed by acetic acid (814 μl, 14.22 mmol). The reaction mixture was stirred at room temperature for 5 minutes before the addition of sodium cyanoborohydride (16.67 mg, 0.265 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was removed and the crude material purified by FCC (50% ethyl acetate/heptane) to afford 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)cyclobutanecarboxylic acid (139 mg, 0.302 mmol, 56.9% yield) as a white solid. LCMS (Table A, Method b) 2.89 min, (M+H)+ 428.20.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].C(NC1C=CC(S([N:27]=[N+:28]=[N-])(=O)=O)=CC=1)(=O)C.C(N(CC)CC)C>C(#N)C>[N+:27](=[C:8]([C:7](=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]([O:11][CH3:12])=[O:10])=[N-:28]
Reactant: COCCCCC(=O)CC(=O)OC
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCCCC(=O)C(=[N+]=[N-])C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 121.8 %

Procedure:
To a solution (100 ml) of methyl 7-methoxy-3-oxoheptanoate (5.00 g) and 4-(acetylamino)benzenesulfonyl azide (7.02 g) in acetonitrile was added triethylamine (11.1 ml) and the mixture was stirred at room temperature for 2 days. Insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was suspended in diethyl ether and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the object product (6.93 g).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH2:9]([O:11][C:12](=[O:24])[CH2:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH3:23])=[CH:16][N:15]=1)[CH3:10]>CN(C=O)C>[CH2:9]([O:11][C:12](=[O:24])[C:13]([C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]([CH3:23])=[CH:16][N:15]=1)=[CH:3][N:4]([CH3:5])[CH3:6])[CH3:10]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)Cc1ncc(C)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)c1ncc(C)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A solution of dimethylformamide dimethyl acetal (4 g, 0.033 mol) in dry DMF (10 mL) is added to a solution of (5-methyl-3-nitro-pyridin-2yl)-acetic acid ethyl ester (5 g, 0.022 mol) in dry DMF (20 mL) to give a red solution. This solution is heated at 60° C. under reduced pressure for 3 h. DMF and other volatile components are evaporated under reduced pressure to obtain 3-dimethylamino-2-(5-methyl-3-nitro-pyridin-2-yl)-acrylic acid ethyl ester as an viscous oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[C:19]=1[O:26][CH3:27].[Cl-].[Al+3].[Cl-].[Cl-].COC1C=CC(OC)=CC=1C(C1C=C(OC)C=C(OC)C=1)=O>C(Cl)Cl>[OH:24][C:20]1[C:19]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:23]=[CH:22][C:21]=1[C:6]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:7]
Reactant: COc1cccc(OC)c1OC
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: COc1cc(OC)cc(C(=O)c2cc(OC)ccc2OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C(=O)c2ccc(OC)c(OC)c2O)cc(OC)c1OC
Yield: 56.5 %

Procedure:
3,4,5-Trimethoxybenzoyl chloride (11.07 g, 48.0 mmol), 1,2,3-trimethoxybenzene (8.07 g, 48.0 mmol) in anhydrous methylene chloride (60 ml), and aluminum chloride (7.04 g, 52.8 mmol) were treated in the same manner as described above for the synthesis of (2,5-dimethoxy-phenyl)-(3,5-dimethoxy-phenyl)methanone. The crude material was purified via flash column chromatography (25% EtOAc in hexane) to give (2-hydroxy-3,4-dimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone as a yellow solid (9.44 g, 54%); mp, 135-1370C: 1HNMR (DMSO-d6) δ 11.39 (s, 1H, OH), 7.35 (d, J=8 Hz, 1H, Ar), 6.97 (s, 2H, Ar), 6.70 (d, J=9 Hz, 1H, Ar), 3.89 (s, 3H, OCH3), 3.81 (s, 6H, 2OCH3), 3.76 (s, 3H, OCH3), 3.74 (s, 3H, OCH3); 13C NMR (DMSO-d6) δ 197.5, 157.6, 154.6, 152.5, 140.8, 136.0, 132.9, 128.7, 115.8, 106.7, 103.6, 60.1, 60.0, 56.0; Anal. Calcd. For C18H20O7: C, 62.06; H, 5.79. Found: C, 62.05; H, 5.55. The product was carried over to the next step.
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1.[Cl:40][CH2:41][S:42](Cl)(=[O:44])=[O:43].C([O-])([O-])=O.[K+].[K+].Cl>C(Cl)Cl.CO>[ClH:40].[Cl:40][CH2:41][S:42]([N:30]1[CH2:31][CH2:32][CH:27]([N:20]([C:10]2[N:9]=[C:8]([N:7]3[C:6]4[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=4[N:4]=[C:3]3[CH:2]([F:1])[F:39])[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=2)[CH2:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:28][CH2:29]1)(=[O:44])=[O:43]
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCNCC2)n1
Reactant: O=S(=O)(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCN(S(=O)(=O)CCl)CC2)n1
Yield: 44 %

Procedure:
Reaction of N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-(4-piperidinyl)-1,3-propanediamine (Example 21) with chloromethanesulfonyl chloride and K2CO3 in CH2Cl2, followed by conversion to the hydrochloride salt with 1.25 M HCl in methanol gave N1-{1-[(chloromethyl)sulfonyl]-4-piperidinyl}-N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-1,3-propanediamine hydrochloride in 44% yield: mp (MeOH) 222-225° C.; 1H NMR (DMSO-d6) δ9.89 (br, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.71 (t, JHF=53.0 Hz, 1H), 7.47-7.41 (m, 1H), 7.00 (d, J=8.2 Hz, 1H), 5.17 and 5.11 (2s, 2H), 4.74-4.71 and 4.66-4.53 (2m, 1H), 3.98 (s, 3H), 3.92-3.82 (m, 6H), 3.71 (m, 4H), 3.60-3.51 (m, 2H), 3.16-3.04 (m, 4H), 2.75 and 2.70 (2s, 6H), 2.02-1.80 (m, 6H); Anal. Calcd. for C27H39Cl2F2N9O4S.0.5 H2O: C, 46.1; H, 5.7; N, 17.9; Cl, 10.1. Found: C, 46.1; H, 5.8; N, 17.9; Cl, 9.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.Cl.[CH3:14][NH:15][O:16][CH2:17][C:18]([OH:20])=[O:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([NH:8][C:9]([N:15]([CH3:14])[O:16][CH2:17][C:18]([OH:20])=[O:19])=[S:10])[CH:7]=1
Reactant: CNOCC(=O)O
Reactant: COc1ccc(Cl)cc1N=C=S
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1NC(=S)N(C)OCC(=O)O
Yield: 97.8 %

Procedure:
A mixture of 5-chloro-2-methoxyphenyl-isothiocyanate (11.45 g), N-methyl aminooxy acetic acid hydrochloride (8.15 g), triethylamine (20 g) and chloroform (250 mL) was heated at reflux for three hours, then evaporated to dryness. The residue was dissolved in ethyl acetate (400 mL) and washed with 2N HCl (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness to give (17.1 g) of [[[[(5-chloro-2-metoxyphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as an oil that solidifies upon standing. The acid (15.2 g) was dissolved in benzene (200 mL). Phosphorus pentachloride (10.4 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (40-60% methylene chloride in hexane). The title compound (5.1 g) was obtained as a solid, m.p. 189-191° C. Mass spectrum (El, M.+) m/z 286/288. 1H-NMR (DMSO-d6; 400 MHz) δ7.44 (d, 1H), 7.31 (s, 1H), 7.14 (d, 1H), 5.06 (s, 2H), 3.73 (s, 3H), and 3.63 ppm (s, 3H).