Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(NC([N:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]1)=O)(C)(C)C.Cl[C:17]1[C:21]([S:22]([CH2:25][CH3:26])(=O)=O)=[N:20][S:19][N:18]=1.I[CH2:28][CH2:29]CC>C1COCC1.CN(C=O)C>[CH2:25]([S:22][C:21]1[C:17]([O:15][CH:12]2[CH2:13][CH2:14][NH:10][CH2:11]2)=[N:18][S:19][N:20]=1)[CH2:26][CH2:28][CH3:29]
Reactant: CCCCI
Reactant: CCS(=O)(=O)c1nsnc1Cl
Reactant: CC(C)(C)NC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCSc1nsnc1OC1CCNC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A suspension of NaH (0.22 g, 0.009 mol) in THF (30 mL) was treated with (±)-1-t-butylcarbamoyl-3-hydroxypyrrolidine (1.73 g, 0.0092 mol), and the reaction heated to reflux for 35 min. After cooling to 10° C., 3-chloro-4-ethylsulfonyl-1,2,5-thiadiazole (1.96 g, 0.0092 mol) in THF (5 mL) was added, cooling was removed, and the reaction heated to 35° C. for 16 h. The reaction was diluted with H2O, ether added, and the ether extract separated. The ether extract was washed with H2O, dried, and the solvent evaporated to give a tan liquid, (3.05 g). A DMF (42 mL) solution of the liquid was treated with freshly ground flaked Na2S-9 H2O (3.3 g, 0.0138 mol). After 1 h, 1-iodobutane (3.42 g, 0.0186 mol) was added, and the reaction stirred at 40° C. for 16 h. The solvent was evaporated, the residue diluted with cold water, and the mixture extracted with ether. The ether was dried, the solvent evaporated, the residue dissolved in ether, and the solution treated with a stream of dry HCl for 5 min. After 66 h, the reaction was treated with ice-water and the organic solvent evaporated. The aqueous solution was extracted with ether, made basic, and extracted with ether. The ether extracts were dried and the solvent evaporated to give a tan liquid that was purified by radial chromatography (5% EtOH-0.5% NH4 OH-CHCl3). The HCl salt (0.67 g) crystallized from EtOAc, m.p. 99°-100.5° C. (Compound 53).
Reaction SMILES: [NH2:1][C:2]([CH2:8][CH3:9])=[CH:3][C:4]([O:6][CH3:7])=[O:5].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[I:19].[O:20]1[CH2:25][C:24](=O)[CH2:23][C:22](=[O:27])[CH2:21]1>C(O)C>[CH2:8]([C:2]1[NH:1][C:24]2[CH2:25][O:20][CH2:21][C:22](=[O:27])[C:23]=2[CH:15]([C:14]2[CH:17]=[CH:18][C:11]([F:10])=[C:12]([I:19])[CH:13]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:9]
Reactant: O=Cc1ccc(F)c(I)c1
Reactant: O=C1COCC(=O)C1
Reactant: CCC(N)=CC(=O)OC
Solvent: CCO
Product: CCC1=C(C(=O)OC)C(c2ccc(F)c(I)c2)C2=C(COCC2=O)N1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
The product from Example 11A (1.4 g, 11 mmol), the product from Example 2C (2.9 g, 11 mmol) and the product from Example 1C (1.0 g, 8.8 mmol) were taken up in ethanol (15 mL), heated at 80° C. for 24 hours, stirred at ambient temperature for 36 hours and concentrated. The residue was purified by chromatography on silica gel eluting with 2% methanol in dichloromethane to provide the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][OH:21])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:36]([NH:38][CH3:39])=[O:37])[N:8]([C:22]4[CH:27]=[CH:26][C:25]([NH:28]C5C=CC=CC=5F)=[CH:24][CH:23]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.BrC1C=CC(N2C(C(NC)=O)=C3C(C=C(N(CCCO)S(C)(=O)=O)C(C4CC4)=C3)=N2)=CC=1.[F:72][C:73]1[CH:79]=[CH:78][C:76](N)=[CH:75][CH:74]=1>>[CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][OH:21])[S:14]([CH3:17])(=[O:15])=[O:16])=[CH:11][C:10]3[C:6](=[C:7]([C:36]([NH:38][CH3:39])=[O:37])[N:8]([C:22]4[CH:23]=[CH:24][C:25]([NH:28][C:76]5[CH:78]=[CH:79][C:73]([F:72])=[CH:74][CH:75]=5)=[CH:26][CH:27]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(F)cc1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccccc2F)cc1
Agent: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccc(F)cc2)cc1

Procedure:
5-Cyclopropyl-2-{4-[(4-fluorophenyl)amino]phenyl}-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide (ii) was prepared similarly to Compound (5) (Method C, Step b) from 2-(4-bromophenyl)-5-cyclopropyl-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide (i) using 4-fluoroaniline instead of 2-fluoroaniline.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:33]([NH2:36])(=[O:35])[CH3:34].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[C:33]([NH:36][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1)(=[O:35])[CH3:34]
Reactant: CC(N)=O
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 110 °C

Procedure:
To a suspension of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 (100 mg, 0.22 mmol), Cs2CO3 (158 mg), acetamide (20 mg), and xantphos (13 mg) in dry 1,4-dioxane (2 mL) was degassed with bubbling N2. Pd2 dba3 was added and the 10 mL tube was sealed and heated at 110° C. for 8 hr. After cooling to room temp., the mixture was diluted with water and extracted with ethylacetate. The combined organics were concentrated and the crude residue obtained purified by reverse phase HPLC to give 151. 1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.65 (m, 2H), 7.62 (m, 2H), 7.35 (m, 2H), 7.17 (m, 1H), 6.51 (br s, 1H), 4.15 (m, 2H), 3.29 (s, 3H), 2.91 (m, 2H), 2.03 (s, 3H) MS: (ESI+) 427.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[C:4]([F:31])[CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=5)=[CH:3][C:4]=4[F:31])[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4F)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)c(F)c2)cn1
Temperature: 25 °C
Yield: 118.2 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 14-5), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (130 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.06 mmol), and potassium carbonate (157 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (368 mg, quant.) in an orange oily form.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Reactant: O=C(Cl)C1CC1
Product: Cc1nc(-c2sc(NC(=O)C3CC3)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and cyclopropanecarbonyl chloride.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.B(O)(O)[C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C1COCC1.[Pd](Cl)Cl>[O:22]1[C:19]2[CH:20]=[CH:21][C:16]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=4)[N:3]=3)=[CH:17][C:18]=2[O:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: Cl[Pd]Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(-c3ccc4c(c3)OCO4)ccc2c1
Yield: 27.2 %

Procedure:
2-chloro-6-nitroquinoline (5.2 g, 25 mmol) (prepared according to Byoung S. L. et al. Heterocycles. 1998, 48.12, 65), 3,4-(methylenedioxy)phenylboronic acid (5.0 g, 30 mmol), palladium dichloride bis(triphenilphosphine) (350 mg, 0.5 mmol) and barium hydroxide octahydrate (18.9 g, 60 mmol) in 150 ml of anhydrous THF are stirred at 65° C. for 20 hours. The mixture of reaction is evaporated under vacuum and the residue is chromatographed on silica gel (CH2Cl2) to afford 2.0 g (27%) of the titled product.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[C:18](#N)C>>[CH3:18][C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Reactant: CC#N
Product: Cc1nsc2nc3ccccc3n12
Yield: 88 %

Procedure:
2-Butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (1.00 g, 4.04 mmol) was refluxed in 100 mL acetonitrile for 18 h. The solvent was then evaporated and the residue was recrystallized from methanol to give 0.671 g (88%) of the title compound: mp 192-193° C.; 1H NMR (CDCl3) δ 7.81 (dm, 2H), 7.47 (td, 1H), 7.34 (td, 1H), 2.92 (s, 3H) ppm; IR (KBr) ν 1564, 1481, 1453, 1430, 1304, 1208, 756, 745 cm-1 ; MS m/z 189 (M+), 148 (M+ --CH3CN)
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=2.Cl.[CH3:32][NH:33][CH3:34].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1>[CH3:32][N:33]([CH3:34])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([CH2:21][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:13])([F:14])[F:15])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH:23]=1
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(C(=O)O)c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 61.2 %

Procedure:
A solution of 60 mg (0.139 mmol) of 3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzoic acid (example 31) in 1 mL of THF was treated with 31 mg (0.417 mmol) of dimethylamine hydrochloride, 0.09 mL (0.834 mmol) of N-methylmorpholine, 3.7 mg (0.028 mmol) of HOBT, and 37 mg (0.195 mmol) of EDCl. The mixture was stirred for 10 hrs at RT and the solvent evaporated. Column chromatography on silica gel with n-heptane/EtOAc 4:1 to 1:1 yielded 39 mg (60%) of N,N-dimethyl-3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzamide, colorless solid, MS: 459 (MH+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](=[O:22])[C:19]([OH:21])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[CH3:23][Si](C=[N+]=[N-])(C)C.C(OCC)C>CO>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([C:18](=[O:22])[C:19]([O:21][CH3:23])=[O:20])=[C:13]([CH3:17])[S:14][C:15]=3[CH3:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1sc(C)c(-c2ccc3c(c2)CCCO3)c1C(=O)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(=O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A solution of 2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethylthiophen-3-yl]-2-oxoacetic acid (42a) (1.09 g, 3.43 mmol) in methanol (10 mL) was cooled to 0° C. Trimethylsilyldiazomethane 2N in diethyl ether (6.89 mL, 13.7 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 3 hours. The precipitate was filtered off and washed with cooled methanol (5 mL). The filtrate was concentrated in vacuo and the residue was dissolved in a minimum of methanol. The solution was sonicated for a few seconds and the precipitate was filtered and washed with cooled methanol. The precipitates were combined to provide the desired ester (42b) (820 mg, 2.48 mmol, 72% over two steps) as a beige solid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[C:5]#[N:6].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl.N1C=CC=CC=1>[Br:10][C:8]1[CH:9]=[C:2]([NH:1][S:12]([CH3:11])(=[O:14])=[O:13])[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cc(N)cc(Br)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)cc(C#N)c1
Reaction time: 6.5 h
Yield: 88 %

Procedure:
To a stirring solution of 502 mg of 3-amino-5-bromobenzonitrile in 6 mL of CH2Cl2 and 2 mL of pyridine at 0° C. was added 0.2 mL (2.57 mmol) of MsCl at 0° C. The ice bath was removed and stirring was continued at r.t. for 6.5 h. The solution was concentrated and EtOAc and 20 mL of H2O were added. The organic layer was washed with 15 mL of brine and water, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (35% EtOAc/hexanes) provided 617 mg of N-(3-bromo-5-cyanophenyl)methanesulfonamide as a colorless solid in 88% yield.
Reaction SMILES: O=[C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:14])[C@H:6]2[C:9]([O:12][CH3:13])([CH3:11])[CH3:10])[C@H:3]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16].C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N:52]1[CH:57]=[CH:56][C:55]([SH:58])=[CH:54][CH:53]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C)C=O>[CH3:13][O:12][C:9]([C@@H:6]1[C:5](=[O:14])[N:4]2[C@@H:7]1[CH2:8][C:2]([S:58][C:55]1[CH:56]=[CH:57][N:52]=[CH:53][CH:54]=1)=[C:3]2[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[O:16])([CH3:11])[CH3:10]
Reactant: COC(C)(C)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: Sc1ccncc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(C)(C)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccncc3)C[C@H]12
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 4-nitrobenzyl (2R, 5R, 6R)-3,7-dioxo-6-(1-methoxy-1-methylethyl)-1-azabicyclo[3.2.0]heptane-2-carboxylate (450 mg) and 4-(N,N-dimethylamino)pyridine (14.6 mg) in methylene chloride (22.5 ml) was added a solution of N,N-diisopropyl-N-ethylamine (0.249 ml) in methylene chloride (2.241 ml) at -30° C. To the mixture was added further a solution of trifluoromethanesulfonic anhydride (0.211 ml) in methylene chloride (1.899 ml) at -30° C. After stirring for 30 minutes at the same temperature, a solution of 4-(N,N-dimethylamino)pyridine (2.9 mg) and N,N-diisopropyl-N-ethylamine (0.0498 ml) in methylene chloride (0.448 ml) and then a solution of trifluoromethanesulfonic anhydride (0.0422 ml) in methylene chloride (0.38 ml) were added thereto at -30° C. After stirring for 30 minutes at the same temperature a solution of N,N-diisopropyl-N-ethylamine (0.833 ml) in methylene chloride (7.497 ml) and a solution of pyridine-4-thiol (159.5 mg) in N,N-dimethylformamide (5.63 ml) were added successively thereto at -30° C. The resultant solution was stirred for 30 minutes at the same temperature and for additional 30 minutes at 0° C. The solvent was distilled off and the residue was dissolved in ethyl acetate, washed twice with water and a saturated aqueous sodium chloride. After drying over magnesium sulfate, the solution was filtered and evaporated. The residue was chromatographed on deactivated silica gel with 10% water (13.5 g), eluting with a mixture of benzene and acetone (100:1 to 6:1) to give 4-nitrobenzyl (5R, 6R)-6-(1-methoxy-1-methylethyl)-7-oxo-3-(4-pyridylthio)-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (379 mg) as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:4][N:3]=1.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([OH:48])[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:33]1>O>[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([O:48][C:2]4[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH:13]5[CH2:18][CH2:17][CH2:16][CH2:15][O:14]5)=[CH:4][N:3]=4)[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:33]1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: Fc1ccc(OCCCOC2CCCCO2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OCCCOC5CCCCO5)cn4)cc23)n1
Temperature: 180 °C
Reaction time: 14 h
Yield: 96.5 %

Procedure:
2-Fluoro-5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridine (305 mg, 1.10 mmol) and potassium tert-butoxide (140 mg, 1.24 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (120 mg, 0.50 mmol), and stirred at 180° C. for 14 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled with ice, then saline water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, chloroform:methanol=100:3) to obtain N-(1-methyl-1H-pyrazol-3-yl)-6-({5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridin-2-yl}oxy)quinazoline-4-amine (230 mg, yield: 97%) as a pale orange amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].II.[I:14](O)(=O)(=O)=O.C(OCC)(=O)C>C(O)C.O>[OH:1][C:2]1[C:9]([I:14])=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C=O)c(O)c1I
Temperature: 68 °C
Yield: 24.6 %

Procedure:
To a solution of 4.0 g (26.3 mmol) of 2-hydroxyl-4-methoxybenzaldehyde in 30 mL of ethanol was added 1.87 g (7.4 mmol) of iodine, followed by addition of a solution of 6 g (26.3 mmol) of periodic acid in 10 mL of water. The resulting dark yellow solution was heated to 68° C. for two h. After cooling to room temperature, the reaction was added to 300 mL of ethyl acetate. The resulting organic solution was washed with saturated aqueous solution of sodium sulfite, washed with brine and dried over anhydrous magnesium sulfate. After removing the volatiles, the crude products were purified by silica chromatography to afford 1.8 g (49%) of a light yellow solid: 1H NMR(CDCl3/400 MHz,) 12.18(s, 1H), 9.63(s, 1H), 7.53(d, J=8.4 Hz, 1H), 6.56(d, J=8.4 Hz, 1H), 3.99(s, 3H). 13C NMR (CDCl3/400 MHz) 194.2, 165.3, 163.0, 136.3, 116.1, 103.6, 57.2. MS (ESI+) 278.9(M+1, 100).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[C:16](=O)[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[BH3-]C#N.[Na+]>CO>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C2CCCC1CN(Cc1ccccc1)C2
Reactant: C1CNCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CN2CC3CCCC(C2)C3N2CCNCC2)cc1

Procedure:
A mixture of 3-benzyl-3-azabicyclo[3.3.1]nonan-9-one (0.72 g, 3.14 mmol), methanol (25 ml), piperazine(2.71 g, 31.4 mmol), several 3A molecular sieves, and NaBH3CN (0.39 g, 6.28 mmol) was refluxed for 60 hr, cooled, and concentrated. The residue was taken up in 1N HCl (50 ml), washed with ethyl acetate, the pH adjusted to 12 with 1N NaOH aqueous solution, and extracted with dichloromethane. The extract was dried over Na2SO4 and concentrated to afford 0.72 g (72% crude) of an oil, which was used directly in the following step.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][C:5]=1[CH2:19][NH:20][CH2:21][CH2:22][CH3:23])([O-])=O.S1C=CC=C1.O=[Si]=O>CO.[Pd]>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][C:5]=1[CH2:19][NH:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCNCc1cc(Oc2cccc(C#N)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=[Si]=O
Solvent: CO
Solvent: c1ccsc1
Product: CCCNCc1cc(Oc2cccc(C#N)c2)ccc1N

Procedure:
A mixture of 3-(4-nitro-3-propylaminomethyl-phenoxy)-benzonitrile (0.045 mol) in methanol (250 mL) was hydrogenated with 10% Pd/C (2 g) as a catalyst in the presence of thiophene solution (2 mL). After uptake of H2 gas (3 equiv.), the reaction mixture was filtered over Dicalite and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: 98:2 CH2Cl2:CH3OH). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [C:1](#[N:3])[CH3:2].S(=O)(=O)(O)[OH:5].[CH2:9]([S:11]([C:14]1[S:18][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:16][C:15]=1[CH:23](O)[CH3:24])(=[O:13])=[O:12])[CH3:10].C([O-])(O)=O.[Na+]>O>[C:1]([NH:3][CH:23]([C:15]1[CH:16]=[C:17]([S:19]([NH2:22])(=[O:20])=[O:21])[S:18][C:14]=1[S:11]([CH2:9][CH3:10])(=[O:12])=[O:13])[CH3:24])(=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1sc(S(N)(=O)=O)cc1C(C)O
Reactant: O=S(=O)(O)O
Reactant: CC#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCS(=O)(=O)c1sc(S(N)(=O)=O)cc1C(C)NC(C)=O
Temperature: 25 °C
Yield: 58 %

Procedure:
To acetonitrile (40 ml) was added concentrated sulfuric acid (8.1 g, 0.0828 mol). Then 5-ethylsulfonyl-4-(1-hydroxyethyl)thiophene-2-sulfonamide (4.14 g, 0.0138 mol) was added and the solution was stirred at room temperature until no starting material remained (48 hours). The solution was neutralized by adding solid NaHCO3 along with water (5 ml). The mixture was filtered and the solids were washed with acetonitrile. The filtrate and washings were concentrated in vacuo to an oil. This residual oil was taken up in ethyl acetate (125 ml). The extract was washed with saturated NaCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo at room temperature, to give 2.74 g (58%) of white solid which was a single product by TLC, m.p. 213-220° C. NMR supported the structure.