Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([O:11][CH2:12][CH:13]1[CH:17]([OH:18])[CH2:16][CH:15]([OH:19])[CH:14]1[CH2:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[OH-].[Li+]>O>[CH2:1]([NH:8][C:9]([O:11][CH2:12][CH:13]1[CH:17]([OH:18])[CH2:16][CH:15]([OH:19])[CH:14]1[CH2:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CCCC=CCC1C(O)CC(O)C1COC(=O)NCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCC=CCC1C(O)CC(O)C1COC(=O)NCc1ccccc1
Yield: 9.2 %

Procedure:
According to the procedures described for 4a the reaction of ester 3b (40 mg, 0.99 mmol) and lithium hydroxide hydroxide (0.40 mL of a 0.5 N solution in H2O, 0.20 mmol) afforded 35.6 mg (92%) of the title compound after purification by flash column chromatography (silica gel, 100% EtOAc).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:15][C:16]([O:18]C)=[O:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:15][C:16]([OH:18])=[O:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CC1(NC(=O)OC(C)(C)C)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CC(=O)O)CCOCC1
Temperature: 60 °C
Yield: 88.8 %

Procedure:
To a solution of methyl 2-(4-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-yl)acetate (0.73 g, 2.67 mmol) in ethanol (5 mL) and water (2 mL) was added potassium hydroxide (0.3 g, 5.34 mmol) at room temperature. Upon completion of addition, the reaction mixture was heated at 60° C. for 4 hours and then partitioned between ethyl acetate (30 mL) and 1N HCl (10 mL). The ethyl acetate layer was separated, washed with brine (20 mL), dried over sodium sulfate and concentrated to yield the title compound (0.615 g) as a white solid. MS found: (M−H)+=258.2.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:10]#[C:11][CH2:12][CH2:13][CH:14]=O)[CH:7]=[CH:8][CH:9]=1)=[CH:2][CH3:3].[Cl-].[CH2:17]([N:21]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:22](=[O:24])[CH3:23])[CH:18]([CH3:20])[CH3:19]>>[CH2:17]([NH:21][C:22](=[O:24])/[CH:23]=[CH:14]/[CH2:13][CH2:12][C:11]#[C:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]=[CH:2][CH3:3])[CH:5]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(=O)N(CC(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC=Cc1cccc(C#CCCC=O)c1
Agent: [Cl-]
Product: CC=Cc1cccc(C#CCC/C=C/C(=O)NCC(C)C)c1

Procedure:
N-isobutyl 7-(3'-propenylphenyl)-(2E)-hepten-6-ynamide was prepared from 5-(3'-propenylphenyl)-4-pentyn-1-al and N-isobutyl acetamidotriphenylphosphonium chloride as in Example 9 and semi-hydrogenated as in Example 9 to give N-isobutyl 7-(3'-propenylphenyl)-(2E,6Z)-heptadienamide.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([CH2:21][C:22](=[O:24])[NH2:23])[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:26][C:27](=O)[C:28]([C:30]1[C:40]2=[C:41]3[C:36](=[CH:37][CH:38]=[CH:39]2)[CH2:35][CH2:34][C:33]([CH3:43])([CH3:42])[N:32]3[CH:31]=1)=O>>[C:1]([O:5][C:6]([CH:8]1[NH:20][CH2:19][C:17]2=[C:18]3[C:13](=[C:14]([C:21]4[C:22](=[O:24])[NH:23][C:27](=[O:26])[C:28]=4[C:30]4[C:40]5=[C:41]6[C:36](=[CH:37][CH:38]=[CH:39]5)[CH2:35][CH2:34][C:33]([CH3:42])([CH3:43])[N:32]6[CH:31]=4)[CH:15]=[CH:16]2)[CH:12]=[CH:11][N:10]3[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2(C)C
Reactant: CC(C)(C)OC(=O)C1Cn2ccc3c(CC(N)=O)ccc(c32)CN1
Product: CC(C)(C)OC(=O)C1Cn2ccc3c(C4=C(c5cn6c7c(cccc57)CCC6(C)C)C(=O)NC4=O)ccc(c32)CN1

Procedure:
Beginning with 7-Carbamoylmethyl-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carboxylic acid tert-butyl ester and (4,4-Dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-oxo-acetic acid methyl ester, the title compound was prepared essentially as Example 1.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH2:13][N+:14]([O-])=O)[CH2:10][C@@H:9]([CH3:11])[C@H:8]([CH3:12])[CH2:7]1)C>CO.[Ni]>[CH3:12][C@H:8]1[C@H:9]([CH3:11])[CH2:10][C:6]2([CH2:13][NH:14][C:4](=[O:3])[CH2:5]2)[CH2:7]1
Reactant: CCOC(=O)CC1(C[N+](=O)[O-])C[C@@H](C)[C@H](C)C1
Agent: [Ni]
Solvent: CO
Product: C[C@@H]1CC2(CNC(=O)C2)C[C@H]1C
Reaction time: 5 h
Yield: 94.9 %

Procedure:
The nitroester (3) (1.14 g, 4.7 mmol) was dissolved in methanol (50 mL) and shaken over Raney nickel catalyst under an atmosphere of hydrogen (40 psi) at 30° C. After 5 hours, the catalyst was removed by filtration through celite. The solvent was removed in vacuo to give 746 mg (95%) of a pale yellow oil which solidified on standing.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([C:11]2[C:19]3[CH:18]=[N:17][CH:16]=[N:15][C:14]=3[N:13]([Si](C(C)C)(C(C)C)C(C)C)[CH:12]=2)O)=[CH:5][N:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]([CH2:9][C:11]2[C:19]3[CH:18]=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)=[CH:7][N:8]=1
Reactant: CSc1ncc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncncc23)cn1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1ncc(Cc2c[nH]c3ncncc23)cn1
Temperature: 80 °C
Yield: 72.9 %

Procedure:
To a solution of (2-methylsulfanyl-pyrimidin-5-yl)-(7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanol (55, 2.75 g, 6.40 mmol) in 50.0 mL of 1,2-dichloroethane, triethylsilane (8.00 mL, 50.1 mmol) and trifluoroacetic acid (4.00 mL, 51.9 mmol) were added. The reaction was heated at 80° C. overnight, then concentrated under vacuum, combined with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 2-15% methanol in dichloromethane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (56, 1.20 g). MS (ESI) [M+H+]+=258.2.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:25][C:26]1[C:31]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)=[CH:16][CH:17]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: OB(O)c1cccnc1F
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccnc5F)n4n3)cc2)CC1

Procedure:
[7-(2-Fluoro-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine and 2-fluoro-3-pyridineboronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (78 mg, 68%). m.p.=201-203° C.; LCMS (m/e) 404 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.95-8.87 (m, 1H), 8.74 (s, 1H), 8.23-8.17 (m, 1H), 7.47 (d, 2H, J=7.7 Hz), 7.34-7.27 (m, 1H), 7.19-7.12 (m, 1H), 6.92 (d, 2H, J=8.0 Hz), 6.85 (d, 1H, J=4.7 Hz), 6.68 (s, 1H), 3.23-3.15 (m, 4H), 2.64-2.56 (m, 4H), 2.37 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][CH2:11][O-:12].[Na+].CCO>CCO>[Cl:1][C:2]1[N:7]=[C:6]([O:12][CH2:11][CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Cl)ncc1F
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of the product from step (a) (10.0 g, 59.9 mmol) in abs. EtOH (40 mL) at 0° C. under nitrogen atmosphere was added 1M NaOEt/EtOH (61 mL, 61 mmol) and the mixture was stirred for 1 hour. Solvent was evaporated in vacuo and the residue partitioned between H2O and Et2O. The aqueous phase was extracted with Et2O and the combined organic phase was washed with brine, dried (Na2SO4) and evaporated (water aspirator pump, 35° C.) to provide the desired product (8.74 g, 83%) as a yellowish solid: mp 30-32° C. (lit. 31-32° C.); 1H NMR (CDCl3): δ 1.46 (t, J=7.0 Hz, 3H), 4.53 (quartet, J=7 Hz, 2H), 8.17 (d, J=2.1 Hz, 1H); MS m/z 179 (M+3, 17%), 177 (M+1, 50%), 149 (100%). Anal. Calcd. for C6H6ClFN2O: C, 40.81; H, 3.42; N, 15.86. Found, C, 40.90; H, 3.45; N, 15.81.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([C@H:19]1[C@@H:23]([C:24]2[N:28]3[C:29]4[CH:35]=[CH:34][N:33]([S:36]([C:39]5[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:30]=4[N:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:22][C:21](=O)[CH2:20]1)[CH3:18].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:17]([C@H:19]1[C@@H:23]([C:24]2[N:28]3[C:29]4[CH:35]=[CH:34][N:33]([S:36]([C:39]5[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=5)(=[O:37])=[O:38])[C:30]=4[N:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:22][C:21](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:20]1)[CH3:18]
Reactant: CC[C@@H]1CC(=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=C1C[C@@H](CC)[C@@H](c2nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n23)C1
Yield: 89.3 %

Procedure:
To a slurry of sodium hydride (0.227 g, 5.67 mmol, 60% dispersion in oil) in THF (30 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (1.18 mL, 5.90 mmol). After about 30 min a solution of (cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (2.00 g, 4.72 mmol) in THF (1.0 mL) was added. After about 4 h EtOAc and sat NaHCO3 were added. The organic layer was separated concd in vacuo and purified by flash chromatography on silica gel eluting with 20-100% EtOAc in DCM to afford ethyl 2-((cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate (2.08 g, 89%): LC/MS (Table 1, Method c) Rt=2.52-2.56 min; MS m/z: 494 (M+H)+ as a mixture of diastereomers and ethyl 2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate (0.150 g, 9%), as a mixture of diastereomers: LC/MS (Table 1, Method a) Rt=1.85-1.89; MS m/z: 340 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])[CH3:3].N1C=CN=C1.[OH:24][C@H:25]([CH2:46][OH:47])[C@H:26]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C=O)C.CCOC(C)=O>[Si:5]([O:47][CH2:46][C@@H:25]([OH:24])[C@H:26]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)([C:2]([CH3:4])([CH3:3])[CH3:1])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1ccc([C@@H](NC(=O)OCc2ccccc2)[C@H](O)CO)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](NC(=O)OCc2ccccc2)[C@H](O)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
TBDPSCl (3.5 g, 12.6 mmol, 1.1 equiv) and imidazole (1.95 g, 28.7 mmol, 2.5 equiv) were added to a solution of 2.21.1b (3.8 g, 11.4 mmol, 1.0 equiv) in DMF (11.5 mL) at room temperature and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl solution, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/heptane, 0 to 50%) to give product 5.4 g (83% yield). MS m/z (M+Na) 592
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[O:13]=[C:14]1[N:20]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C@@H:30]([C:42](O)=[O:43])[CH2:31][C:32]3[CH:37]=[C:36]([CH3:38])[C:35]([OH:39])=[C:34]([CH2:40][CH3:41])[CH:33]=3)=[O:28])[CH2:23][CH2:22]2)[CH2:19][CH2:18][C:17]2[CH:45]=[CH:46][CH:47]=[CH:48][C:16]=2[NH:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:13]=[C:14]1[N:20]([CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C@H:30]([CH2:31][C:32]3[CH:37]=[C:36]([CH3:38])[C:35]([OH:39])=[C:34]([CH2:40][CH3:41])[CH:33]=3)[C:42](=[O:43])[N:10]3[CH2:11][CH2:12][N:7]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH2:8][CH2:9]3)=[O:28])[CH2:25][CH2:26]2)[CH2:19][CH2:18][C:17]2[CH:45]=[CH:46][CH:47]=[CH:48][C:16]=2[NH:15]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: CCc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Reaction time: 2 h

Procedure:
30 mg (0.18 mmol) 1-(tetrahydropyran-4-yl)-piperazine were added at RT to a solution of 80 mg (0.16 mmol) (R)-1-carboxy-2-(3-ethyl-4-hydroxy-5-methyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 57 mg (0.18 mmol) TBTU and 28 μL (0.20 mmol) triethylamine in 1 mL DMF and the reaction mixture was stirred for 2 h. The reaction solution was purified by HPLC without any further working up, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:15])=[CH:9]2)[CH2:2][CH2:3][CH3:4].CC1NC2C(C=1[CH:26]=[O:27])=CC(OCCC)=CC=2>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:15])=[C:9]2[CH:26]=[O:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2[nH]c(C)cc2c1
Reactant: CCCOc1ccc2[nH]c(C)c(C=O)c2c1
Product: CCCCOc1ccc2[nH]c(C)c(C=O)c2c1
Yield: 94 %

Procedure:
This compound was prepared from 408d (300 mg, 1.48 mmol) in a manner similar to that for 409b to yield a cream-colored powder (320 mg, 94%): mp 160-161° C. TLC Rf 0.45 (3:1 EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 11.85 (s, 1H), 10.00 (s, 1H), 7.55 (d, 1H, J=2.46 Hz), 7.26-7.25 (d, 1H, J=8.7 Hz), 6.79-6.77 (dd, 1H, J1=8.7 Hz, J2=2.46 Hz), 3.96-3.94 (t, 2H, J=6.48 Hz), 2.64 (s, 3H), 1.73-1.68 (quin, 2H, J=6.48 Hz), 1.49-1.42 (sex, 2H, J=7.38 Hz), 0.95-0.93 (t, 3H, J=7.38 Hz). 13C NMR (150 MHz, d6-DMSO) δ 185.0, 154.9, 148.5, 130.0, 126.4, 113.6, 112.26, 112.04, 103.2, 67.4, 31.0, 18.8, 13.8, 11.5. Elemental analysis calculated for C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.87; H, 7.47; N, 6.13.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[OH:9][C:10]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=1[C:17](=[O:19])[CH3:18]>CN(C=O)C>[CH3:1][O:16][C:14]1[CH:13]=[CH:12][C:11]([C:17](=[O:19])[CH3:18])=[C:10]([OH:9])[CH:15]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=O)c(O)c1
Reaction time: 4 h

Procedure:
Potassium carbonate (27.2 g, 197 mmol) followed by methyl iodide (4.1 mL, 65.7 mmol) were added to a solution of 2′,4′-dihydroxyacetophenone (10.0 g, 65.7 mmol) in DMF (100 mL). The mixture was stirred for 4 hours and then partitioned between H2O and EtOAc. The organic layer was washed with satd NaHCO3, brine, dried over Na2SO4 and concentrated to a clear oil (11.0 g). 1H NMR (300 MHz, CDCl3): δ 2.60- (s, 3 H), 3.80 (s, 3 H), 6.40 (s, 1 H) 6.51 (d, J=2.45 Hz, 1 H), 7.62 (d, J=8.67 Hz, 1 H), 12.90 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(=S)=S>[Br:10][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=1[OH:9]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: S=C=S
Product: Cc1cc(C)c(Br)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 3,5-dimethylphenol (15.0 g, 123 mmol) in carbon disulfide (330 mL) was slowly added N-bromosuccinimide (21.9 g, 123 mmol) in several batches with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the precipitated crystals were filtered and then were washed with ethyl acetate-hexane (10:1). The solution was concentrated, and the residue was purified by silica gel chromatography (ethyl-acetate:hexane=1:9) to obtain 16.3 g (yield 66%) of the title compound. Oily matter.
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH:18]O>C(O)(=O)C>[CH2:1]([C:12]1[CH:13]=[N+:14]([O-:18])[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: OO
Reactant: CCCCCCCCCCCc1cccnc1
Solvent: CC(=O)O
Product: CCCCCCCCCCCc1ccc[n+]([O-])c1
Yield: 86.8 %

Procedure:
A solution of 11.0 g (47 mmol) of 3-n-undecylpyridine and 8 ml of an aqueous 35% hydrogen peroxide dissolved in 30 ml of glacial acetic acid was heated at 70° to 80° C. for 3 hours, and then further heated with an additional 3 ml of hydrogen peroxide at the same temperature for 9 hours. After cooling, the mixture was concentrated under a reduced pressure to about a half amount, and 50 ml of water was added, followed by a concentration to a half amount (repeated twice). The residue was extracted with diethyl ether and washed with sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the product was concentrated under a reduced pressure, and the residue was purified by separation according to silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=15:85) to obtain 10.2 g of the desired product (yield 86.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:19])([CH3:18])[C:12](=[O:17])[CH2:13][N+:14]([O-])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H].[ClH:22]>C(O)(=O)C.[Pd]>[ClH:22].[NH2:14][CH2:13][C:12](=[O:17])[C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:19])[CH3:18]
Reactant: [H][H]
Reactant: COc1ccc(C(C)(C)C(=O)C[N+](=O)[O-])cc1OC
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc(C(C)(C)C(=O)CN)cc1OC
Yield: 75 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-3-methyl-1-nitrobutan-2-one (400 mg, 1.50 mmol) in acetic acid (6 mL) and conc HCl (2 mL) was added 10% Pd/C (400 mg) in a pressure vessel. The mixture was hydrogenated under 60 psi hydrogen for 48 h and then filtered. The residue was concentrated and triturated with Et2O to give 1-amino-3-(3,4-dimethoxyphenyl)-3-methylbutan-2-one hydrochloride (306 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ 8.22 (brs, 2H), 6.90 (d, 1H), 6.80 (dd, 1H), 6.72 (d, 1H), 3.73 (s, 3H), 3.70 (s, 3H), 3.68 (s, 2H), 1.42 (s, 6H).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[O:54][C:55]3[CH:65]=[CH:64][C:63]([C:66]4[CH:67]=[C:68]([CH:72]=[CH:73][CH:74]=4)[C:69](O)=[O:70])=[CH:62][C:56]=3[C:57]=2[C:58](=[O:61])[NH:59][CH3:60])=[CH:49][CH:48]=1>CN(C=O)C>[F:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[O:54][C:55]3[CH:65]=[CH:64][C:63]([C:66]4[CH:74]=[CH:73][CH:72]=[C:68]([C:69](=[O:70])[NH:12][C:9]([C:6]5[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=5)([CH3:11])[CH3:10])[CH:67]=4)=[CH:62][C:56]=3[C:57]=2[C:58]([NH:59][CH3:60])=[O:61])=[CH:49][CH:48]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: CC(C)(N)c1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccncc4)c3)cc12
Reaction time: 1 h
Yield: 28.7 %

Procedure:
2-(pyridin-4-yl)propan-2-amine dihydrochloride (26 mg, 0.123 mmol) was added to a stirring solution of HATU (59 mg, 0.154 mmol), DIEA (54 μL, 0.308 mmol), and 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (40 mg, 0.103 mmol) in DMF (1 mL) at rt. It was allowed to stir for 1 hour. The reaction was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (15 mg, 27%). 1H NMR (500 MHz, DMSO-d6) d ppm 8.73 (1H, s), 8.50-8.55 (1H, m), 8.48 (2H, dd, J=4.58, 1.53 Hz), 8.16 (1H, s), 7.97-8.04 (2H, m), 7.91-7.94 (1H, m), 7.88 (1H, d, J=7.63 Hz), 7.85 (1H, d, J=7.93 Hz), 7.75-7.82 (2H, m), 7.58 (1H, t, J=7.63 Hz), 7.36-7.43 (4H, m), 2.86 (3H, d, J=4.58 Hz), 1.68 (6H, s). LC-MS retention time: 1.59 min; m/z (MH+): 508. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=8.60 min, purity=95%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=9.26 min, purity=96%.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:19]([NH:22][C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=3)[N:27]=2)(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>C(#N)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:19]([N:22]([C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=3)[N:27]=2)[CH3:1])(=[O:21])=[O:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N(C)c2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1OC
Reaction time: 2 h
Yield: 6.8 %

Procedure:
Anhydrous potassium carbonate (0.204 g, 14.8 mmol), and methyl iodide (0.209 g, 14.8 mmol) were added to a stirred solution of 3,4-dimethoxy-N-(4-(3-nitrophenyl)thiazol-2-yl)benzenesulfonamide (0.250 g, 5.94 mmol) in acetonitrile (10 mL) under a nitrogen atmosphere at room temperature. After 2 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. The crude reaction mixture was subjected to purification by column chromatography on silica gel. Elution with an ethyl acetate-hexane mixture (20:80) gave 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]-N-(methyl)benzenesulfonamide (0.175 g) as a white colored solid.