Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=1[C:32](=[O:34])[CH3:33])(=O)C.[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([CH:44]=O)[CH:42]=[CH:43][C:36]1=2.[OH-].[K+]>[Pt].C(O)C>[C@@H:6]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=2[C:32](=[O:34])[CH2:33][CH2:44][C:41]2[CH:42]=[CH:43][C:36]3[O:35][CH:39]=[CH:38][C:37]=3[CH:40]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=Cc1ccc2occc2c1
Agent: [Pt]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(CCc1ccc2occc2c1)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a mixture of 2'-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6'-hydroxyacetophenone (1500 mg), benzo[b]furan-5-carbaldehyde (545 mg) and ethanol (15 ml) is added dropwise a 50% aqueous potassium hydroxide solution (3 ml), and the mixture is stirred at room temperature overnight. The mixture is subjected to catalytic hydrogenation by using as a catalyst 10% platinum on activated carbon (303 mg) under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue are added toluene and water, and the mixture is stirred. The aqueous layer is collected by filtration, acidified with a 10% hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The obtained organic layer is washed with water, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography to give 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)propiophenone (982 mg). The physical properties of this product are the same as those of the compound of Example 1.
Reaction SMILES: [H-].[Na+].O1CCCC1.[Cl:8][C:9]1[C:10]([CH3:15])=[N:11][O:12][C:13]=1[NH2:14].Cl[S:17]([C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([O:27]C)=[O:26])(=[O:19])=[O:18]>CCCCCC>[Cl:8][C:9]1[C:10]([CH3:15])=[N:11][O:12][C:13]=1[NH:14][S:17]([C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([OH:27])=[O:26])(=[O:18])=[O:19]
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)O)c1Cl
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a mixture of sodium hydride (60%, 2.1 g, 52 mmol) and tetrahydrofuran (20 mL) was added a mixture of 4-chloro-3-methyl-1,2-oxazol-5-amine (3.0 g, 23 mmol) and tetrahydrofuran (20 mL) at 0° C., followed by stirring at that temperature for 30 minutes. Methyl 3-(chlorosulfonyl)thiophene-2-carboxylate (5.3 g, 22 mmol) was added at that temperature to the reaction mixture, which was then stirred for 1 hour at 0° C., and then stirred for 4 hours at room temperature. Hexane (100 ml) was added at room temperature to the reaction mixture, and the precipitated solid was collected by filtration. Methanol (20 mL) was added to the solid, followed by a 2N aqueous solution of sodium hydroxide (20 mL), and the reaction mixture was stirred for 5 hours at room temperature. The solvent was distilled away under reduced pressure, and ice water (20 mL) was added to the residue, followed by a 2 N aqueous solution of hydrochloric acid (20 mL). The precipitated solid was collected by filtration to give the title compound (2.5 g, 35% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=S)=[N:7]1.[NH3:20]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:20])=[N:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[N:7]1
Reactant: OCCCCn1ccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Product: NC(=NCC(F)(F)F)Nc1ccn(CCCCO)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Mercuric oxide (30.1 g.) was added quickly to a stirred solution of 1-(4-hydroxybutyl)-3-(3-[2,2,2-trifluoroethyl]thioureido)pyrazole (10.4 g.) in methanolic ammonia (5N., 340 ml.). After stirring for 3 hours at room temperature, the mixture was filtered through a pad of diatomaceous earth and the filtrate was evaporated in vacuo to give 1-(4-hydroxybutyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole, m.p. 105°-106° (yield 82%).
Reaction SMILES: C1CCCCCCC1.N(OC(C)(C)C)=O.ON1[C:21](=O)[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C1(=NO)CCCCCCC1.[N+](C1CCCCCCC1)([O-])=O>C(O)(=O)C>[C:18]1(=[O:27])[CH2:19][CH2:26][CH2:25][CH2:24][CH2:23][CH2:20][CH2:21]1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)(C)ON=O
Agent: O=[N+]([O-])C1CCCCCCC1
Agent: ON=C1CCCCCCC1
Solvent: C1CCCCCCC1
Solvent: CC(=O)O
Product: O=C1CCCCCCC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Cyclooctane (2 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cyclooctanone oxime, nitrocyclooctane, and cyclooctanone were formed in yields of 64%, 4%, and 2%, respectively.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].C([O-])([O-])=O.[K+].[K+].[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1>CS(C)=O.O>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1
Reactant: c1cc[nH]c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2cccc2)c(F)c1
Temperature: 90 °C
Yield: 97 %

Procedure:
To a solution of 1,2-difluoro-4-nitrobenzene (1.59 g, 10 mmol) in DMSO (15 mL) were added K2CO3 (3.04 g, 22 mmol) and pyrrole (0.74 g, 11 mmol) with stirring. The reaction mixture was heated at 90° C. for 18 h, and cooled to rt. The mixture was diluted with water (50 mL), filtered and the filter cake was dried to give the title compound as a yellow solid (2.00 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)[CH2:4][CH:3]=1.[CH2:16]([CH:19]([CH2:22]O)[CH2:20][OH:21])[CH2:17][CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[O:21][CH2:20][C@H:19]([CH2:16][CH2:17][CH3:18])[CH2:22][O:15]3)[CH2:10][CH2:9]2)[CH2:4][CH:3]=1
Reactant: CCCC(CO)CO
Reactant: O=C[C@H]1CC[C@H](C2CC=C(F)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC[C@H]1CO[C@H]([C@H]2CC[C@H](C3CC=C(F)CC3)CC2)OC1

Procedure:
500 mg of trans-4-(4-fluoro-cyclohex-3-enyl)cyclohexanecarbaldehyde, 310 mg of 2-propyl-propane-l,3-diol and 50 mg of p-toluenesulphonic acid in 8 ml of toluene were boiled at reflux for 1 hour in an apparatus which was gassed with nitrogen and which was fitted with a water separator. After cooling the reaction solution was partitioned in water/ether. The organic phase was washed twice with water. The aqueous phases were extracted twice with ether. The organic phases were combined, dried over magnesium sulphate, filtered and the filtrate was evaporated. The crude product was recrystallized several times from ethanol/1% ethyl acetate and gave 350 mg of trans-2-[trans-4-(4-fluoro-cyclohex-3-enyl)cyclohexyl]-5-propyl-[1,3]-dioxane, m.p. (C-N)<room temperature; S-N 104° C., c1.p. (N-I) 118.3° C.;
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][N:3]=1.O.[NH2:17][NH2:18]>CO>[NH:17]([C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[C:8](=[O:14])[N:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][N:3]=1)[NH2:18]
Reactant: NN
Reactant: Cn1c(=O)c2c(Cl)nccc2n(C)c1=O
Solvent: O
Solvent: CO
Product: Cn1c(=O)c2c(NN)nccc2n(C)c1=O
Yield: 93.1 %

Procedure:
0.69 g of Compound 17 and 0.31 g of hydrazine hydrate were added to 20 ml of methanol and the solution was heated under reflux for 24 hr. The solvent was distilled off to give 0.63 g of 5-hydrazino-1,3-dimethylpyrido[4,3-d]pyrimidine-2,4-dione (Compound 18).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].FC(F)(F)C(O)=O.CO[CH2:18][N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][Si](C)(C)C>C(Cl)Cl>[CH2:25]([N:19]1[CH2:20][CH:4]2[C:3](=[O:8])[N:2]([CH3:1])[C:6](=[O:7])[CH:5]2[CH2:18]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1C(=O)C=CC1=O
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C2CN(Cc3ccccc3)CC2C1=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
N-Methylmaleimide (23.3 g, 21 mmol; Aldrich) was dissolved in CH2Cl2 (400 mL) in a 3-neck flask, chilled to 0° C. under nitrogen, and treated with trifluoroacetic acid (1.6 mL, 21 mmol; Aldrich). A solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (49.8 g, 21 mmol; Aldrich) in CH2Cl2 (60 mL) was then added slowly at a rate to maintain the temperature below about 5° C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred for 24 h. The solution was concentrated under vacuum, and the residue was diluted with CH2Cl2 (125 mL), washed with saturated aqueous NaHCO3 (2×100 mL) and brine (2×100 mL). The organic phase was concentrated under vacuum to afford the title compound as a white solid (51.2 g, 21 mmol; 100% yield): 1H NMR (300 MHz, CDCl3) δ ppm 7.14-7.37 (m, 5H), 3.57 (s, 2H), 3.28 (d, J=10.2 Hz, 2H), 3.13-3.21 (m, 2H), 3.01 (s, 3H), 2.32-2.42 (m, 2H); MS (DCI/NH3) m/z 245 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[N:19]=1.O>CS(C)=O>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[N:19]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1cccc(Cl)n1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(N2CCC(NC(C)=O)CC2)n1
Temperature: 130 °C
Reaction time: 50 h
Yield: 43 %

Procedure:
A mixture of 0.088 mole of 4-acetamidopiperidine, 15 g of potassium carbonate, 0.088 mole of 2-chloro-6-methoxypyridine in 100 ml of dimethylsulfoxide is heated with stirring to 130° C. for 50 hours, then it is cooled, the mixture is poured into water and the suspension thus obtained is extracted with diethyl ether. The aqueous phase is extracted with methylene chloride, the organic phase is washed with water, it is dried on anhydrous sodium sulfate and evaporated to dryness. 4-acetamido-1-(6-methoxy-2-pyridyl)piperidine is thus obtained which, after crystallisation in 95% ethanol, melts at 125° to 127° C.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:14])=[C:7]([C:11]([OH:13])=O)[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3].[OH:15][C:16]1[C:25]([CH2:26][CH3:27])=[CH:24][C:19]([C:20]([NH:22]O)=[NH:21])=[CH:18][C:17]=1[CH2:28][CH3:29]>>[CH2:28]([C:17]1[CH:18]=[C:19]([C:20]2[N:22]=[C:11]([C:7]3[S:8][C:9]([CH3:10])=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6]=3[CH3:14])[O:13][N:21]=2)[CH:24]=[C:25]([CH2:26][CH3:27])[C:16]=1[OH:15])[CH3:29]
Reactant: Cc1sc(C(=O)O)c(C)c1CC(C)C
Reactant: CCc1cc(C(=N)NO)cc(CC)c1O
Product: CCc1cc(-c2noc(-c3sc(C)c(CC(C)C)c3C)n2)cc(CC)c1O

Procedure:
2,6-Diethyl-4-[5-(4-isobutyl-3,5-dimethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenol is prepared from 4-isobutyl-3,5-dimethyl-thiophene-2-carboxylic acid and 4,N-dihydroxy-3,5-diethyl-benzamidine in analogy to Example 21; LC-MS: tR=1.24 min, [M+1]=385.28.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:10][S:11]([O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)(=[O:13])=[O:12]
Reactant: CC1(C)OCC(CO)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OCC(COS(C)(=O)=O)O1
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (400 mg, 3.03 mmol) in DCM (6 mL) at 0° C. was added methanesulfonyl chloride (381 mg, 3.33 mmol) and triethylamine (368 mg, 3.63 mmol. The cold bath was removed and the reaction mixture was stirred for 30 minutes. The mixture was diluted with DCM (5 mL). The organic phase was washed with water (4 mL) and brine (2 mL), and dried (Na2SO4). The solution was concentrated under reduced pressure to give the product (642 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Reactant: O=S1(=O)CCCO1
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CC=C(c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (1.96 g, 13.7 mmol) in acetone (30 mL) was added 1,3-propane sultone (1.74 g, 14.5 mmol). The mixture was stirred at reflux overnight. Only a small amount of compound precipitated. The resulting suspension was cooled to room temperature with stiffing and a larger amount of solid precipitated. The suspension was heated with the addition of a small amount of MeOH until complete dissolution of the solid. The resulting solution was stirred at reflux for a few minutes and was cooled to room temperature with stiffing. The solid was collected by filtration, washed with MeOH and dried in vacuo. This allowed the isolation of compound F, 1.33 g (32%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:35](O)(=O)C.C([BH3-])#N.[Na+]>ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])[CH3:35])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a suspension of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1000 mg) and paraformaldehyde (138 mg) in dichloromethane (20 ml) were added acetic acid (0.26 ml) and sodium cyanoborohydride (144 mg) in an ice bath. The mixture was stirred at room temperature overnight and then methanol (20 ml) was added. The resulting mixture was stirred at 30° C. for 5 hours. The reaction mixture was partitioned between water and ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/2 as an eluant to give the desired compound (761 mg, yield 74%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([S:26]([NH2:25])(=[O:28])=[O:27])=[CH:30][CH:31]=3)[CH:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(S(N)(=O)=O)cc3)c2)n1

Procedure:
The title compound was prepared from 2′-chloro-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.28) (0.150 g, 0.430 mmol) and commercially available (4-aminosulfonylphenyl)boronic acid [CAS-No. 613660-87-0] (0.146 g, 0.516 mmol) according to the general procedure VI. Obtained as a white solid (0.075 g, 37%). MS (ISP) 470.3 [(M+H)+].
Reaction SMILES: FC1C=CC(C[O:7][C:8](=[O:35])[C:9]2[C:10](=[CH:22][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:24][CH:25]=2)[C:11]([O:13]CC2C=CC(F)=CC=2)=[O:12])=CC=1>O1CCCC1.O>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][O:26][C:23]2[CH:22]=[C:10]([C:11]([OH:13])=[O:12])[C:9](=[CH:25][CH:24]=2)[C:8]([OH:35])=[O:7])=[CH:33][CH:32]=1
Reactant: O=C(OCc1ccc(F)cc1)c1ccc(OCc2ccc(F)cc2)cc1C(=O)OCc1ccc(F)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCc2ccc(F)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
A mixture of 4-(4-fluoro-benzyloxy)-phthalic acid bis-(4-fluoro-benzyl) ester (7.8 g, 15.4 mmol) lithium hydroxide monohydrate (1.8 g, 46.2 mmol) in tetrahydrofuran (60 mL) and water (60 mL) was stirred at room temperature for 72 h. The mixture was then evaporated followed by acidification to pH 2 at 0° C. with concentrated HCl. The organic layer was then diluted with ethyl acetate, separared, washed with water and dried over sodium sulfate. Filtration and half evaporation gave a white suspension which was filtered off and washed with ether to afford the title compound (2.5 g, 56%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[NH2:17].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][N:26]=[C:27]=S>C(#N)C>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH:26][C:27]1[NH:1][C:2]2[C:7]3[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=3[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=2[N:17]=1
Reactant: S=C=NCc1ccccc1Cl
Reactant: COC(=O)c1cc(N)c(N)c2c1OC(C)(C)C2
Solvent: CC#N
Product: COC(=O)c1cc2nc(NCc3ccccc3Cl)[nH]c2c2c1OC(C)(C)C2
Yield: 48.9 %

Procedure:
The title compound was prepared following the procedure described for Step-1 of Intermediate-3 using methyl 4,5-diamino-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylate (Intermediate-1, 2.5 g, 10.59 mmol), 1-chloro-2-(isothiocyanatomethyl)benzene (2.5 g, 13.6 mmol), N,N-di-isopropyl carbodimide (0.5 mL) and acetonitrile (10.0 mL) to afford 2.00 g of the desired product. 1HNMR (DMSO-d6): δ 1.41 (s, 6H), 3.00 (s, 2H), 3.71 (s, 3H), 4.60 (d, J=5.3 Hz, 2H), 7.30-7.45 (m, 5H), 7.55 (t, J=6.6 Hz), 10.80 (s, 1H); MS [M+H]+: 386.05.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3](=[O:28])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:40]1[C:41]2[C:48]([CH3:49])=[CH:47][NH:46][C:42]=2[N:43]=[CH:44][N:45]=1>C(O)(C)C>[CH3:1][N:2]([CH3:29])[C:3](=[O:28])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][CH2:18][N:17]([C:40]3[C:41]4[C:48]([CH3:49])=[CH:47][NH:46][C:42]=4[N:43]=[CH:44][N:45]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(OCc3ccccc3)CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(OCc4ccccc4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 110 °C

Procedure:
To a solution of 3-(4-(benzyloxy)piperidine-4-carboxamido)phenyl dimethylcarbamate, from step E, and N,N-diisopropylethylamine (0.7 mL, 4.02 mmol) in isopropanol (1.6 mL) was added 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (135 mg, 0.804 mmol). The reaction mixture was heated to 110° C. in a sealed high-pressure vial for 17 hours, during which time the mixture became homogenous. The reaction was concentrated under vacuum, and half of the material was purified by prep HPLC (30×100 mm C18 column, 20-100% acetonitrile:water (10 mM ammonium acetate), 15 min, 45 mL/min) to afford the title compound (33.4 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4].CO.[Na].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28]>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=2[C:9]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:28][CH2:27][N:29]([CH2:33][CH3:34])[CH2:30][CH3:31])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(O)cc1
Reactant: CCN(CC)CCCl
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCc1oc2ccccc2c1S(=O)(=O)c1ccc(OCCN(CC)CC)cc1

Procedure:
To a solution of 1.4 g. (0.0042 mol.) of 2-n-butyl-3-(4-hydroxyphenylsulfonyl)benzofuran in 20 ml. of methanol was added 25 ml. of methanol containing 110 mg. (0.0048 g.-atom) of sodium. The reaction mixture was heated on a steam bath for 30 minutes then evaporated to dryness. The residue was dissolved in 25 ml. of toluene and ca. 1 ml. of methanol, a suspension of 0.615 g. (0.0048 mol.) of distilled 2-diethylaminoethyl chloride in 15 ml. of toluene was added and the resulting mixture was heated on a steam bath for 3 hours. The solution was filtered through MgSO4 and chromatographed on silica gel with 50:50 ether-acetone to give the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](=[O:16])(Cl)[S:11][CH:12]([CH3:14])[CH3:13].[Br:17][C:18]1[N:22]2[N:23]=[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:25]=[CH:26][C:21]2=[N:20][CH:19]=1>C(OCC)(=O)C>[Br:17][C:18]1[N:22]2[N:23]=[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:10](=[O:16])[S:11][CH:12]([CH3:14])[CH3:13])[CH2:31][CH2:32]3)[CH:25]=[CH:26][C:21]2=[N:20][CH:19]=1
Reactant: CC(C)SC(=O)Cl
Reactant: Brc1cnc2ccc(N3CCNCC3)nn12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)SC(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Hunig's base [7087-68-5] (0.4 mL, 2.4 mmol), then S-isopropyl carbonochloridothioate [13889-93-5] (0.2 mL, 1.6 mmol) were added to a stirred, ambient temperature solution of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine (450.0 mg, 1.6 mmol) in ethyl acetate (30 mL). Then rapidly formed suspension was stirred overnight, under N2 blanket, then washed with brine, dried (MgSO4), evaporated, and crystallized from ethyl acetate/heptane to afford 482.9 mg of white powder, mp. 186-187° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.82 Hz, 6H) 2.51 (dt, J=3.60, 1.86 Hz, 1H) 3.49-3.59 (m, 1H) 3.59-3.71 (m, 7H) 7.58 (d, J=9.85 Hz, 1H) 8.09-8.13 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 23.22, 35.48, 44.71, 101.63, 110.84, 113.71, 114.69, 116.58, 119.46, 123.56, 126.04, 134.22, 155.61, 157.77, 158.15, 158.53, 158.90, 166.18. LRMS (ESI) m/z 384.0/386.0 [(M+H)]+, calc'd for C14H15BrN6OS: 384.30.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[CH2:30](N)[CH2:31][NH2:32]>>[NH:5]1[CH2:30][CH2:31][N:32]=[C:4]1[C:3]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:9][C:2]=1[NH2:1]
Reactant: N#Cc1ccc(N2CCOCC2)cc1N
Reactant: NCCN
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: Nc1cc(N2CCOCC2)ccc1C1=NCCN1
Temperature: 140 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a solution of 2-amino-4-(morpholin-4-yl)benzonitrile 3.65 g (18.0 mmol) in ethylenediamine 20 mL was added phosphorus pentasulfide 4.00 mg (0.018 mmol) and stirred at 140° C. for 16 hours. After cooling to room temperature, the solvent was evaporated. The residue was washed with water and diethyl ether to give the title compound 3.70 g as off-white solid. Yield 83.5%.