Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:14])([CH3:13])[NH:9][CH2:10]2)=[CH:5][C:4]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Cl>CCO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:13])([CH3:14])[N:9]([CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([O:27][CH3:26])[CH:29]=3)[CH2:10]2)=[CH:5][C:4]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19]
Reactant: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)NC2
Reactant: COc1cccc(CCl)c1
Solvent: CCO
Product: COc1cccc(CN2Cc3cc(OC)c(O[Si](C(C)C)(C(C)C)C(C)C)cc3CC2(C)C)c1
Temperature: 130 °C
Yield: 61.3 %

Procedure:
A mixture of 225 (300 mg, 0.83 mmol), 3-methoxybenzyl chloride (0.13 ml, 0.91 mmol) and TEA (0.3 ml, 1.65 mmol) in EtOH (3 ml) was heated in the microwave at 130° C. for 1.5 h. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in EtOAc (30 ml), washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. Purification (flashmaster: 20 g, 100% hex to 50% hex/50% EtOAc and then to 100% EtOAc) afforded the title compound (246 mg, 62%) as colourless oil. 1H NMR (270 MHz; CDCl3) 1.04 (18H, d, J=6.7 Hz, CH3CH), 1.12-1.22 (3H, m, 3×SiCHCH3), 1.17 (6H, s, 2×CH3), 2.65 (2H, s, CH2), 3.47 (2H, s, CH2), 3.64 (2H, s, CH2), 3.74 (3H, s, OCH3), 3.79 (3H, s, OCH3), 6.41 (1H, s, CH), 6.48 (1H, s, CH), 6.77 (1H, ddd, J=8.2, 2.2, 1.2 Hz, CH), 6.95-6.98 (2H, m, 2×CH), 7.22 (1H, t, J=8.2 Hz, CH). 13C NMR (67.5 MHz; CDCl3) 12.38 (CH), 17.49 (CH3), 23.26 (CH3), 42.28 (CH2), 49.64 (CH2), 52.11 (C), 53.22 (CH2), 54.72 (OCH3), 55.04 (OCH3), 111.42 (CH), 111.69 (CH), 113.77 (CH), 117.21 (CH), 120.56 (CH), 125.68 (C), 126.34 (C), 128.69 (CH), 142.09 (C), 142.89 (C), 148.66 (C), 159.15 (C). LC/MS (ES+) tr=4.54 min, m/z 484.83 (M++H). HRMS (ES+) calcd. for C29H46NO3Si (M++H) 484.3241, found 484.3242.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:14]=O)=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>CO>[N+:1]([C:4]1[C:5]([CH2:14][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2]
Reactant: Nc1ccccc1
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1c(CNc2ccccc2)ccc2cccnc12
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A solution of 8-nitro-quinoline-7-carbaldehyde (Intermediate 204) (500 mg, 2.4 mmol) and aniline (270 μl, 2.9 mmol) in MeOH (20 ml) under a nitrogen atmosphere was stirred at room temperature for 16 hours. Sodium borohydride (269 mg, 7.1 mmol) was added and stirring continued at room temperature for 1 h. The reaction mixture was concentrated in vacuo and residue was diluted with sat. NaHCO3 solution (30 ml) and was extracted with DCM. The organic phases were dried (MgSO4) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane/EtOAc gradient elution to give the title compound (0.48 g, 69%).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[N+:8]([C:11]1[CH:12]=[C:13]([CH:31]=[CH:32][CH:33]=1)[CH2:14][NH:15][CH2:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][CH:22]=1)([O-:10])=[O:9].N1C=CC=CC=1.C(OC(=O)C)(=O)C>C(#N)C.CN(C)C1C=CN=CC=1>[C:3]([N:15]([CH2:16][C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])[CH:20]=[CH:21][CH:22]=1)[CH2:14][C:13]1[CH:31]=[CH:32][CH:33]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)(=[O:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CNCc2cccc([N+](=O)[O-])c2)c1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cccc(NC(=O)OC(C)(C)C)c1)Cc1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A solution of tert-butyl (3-{[(3-nitrobenzyl)amino]methyl}phenyl)carbamate trifluoroacetate (0.16 g, 0.34 mmol) in acetonitrile (5.2 mL) was treated with 4-dimethylaminopyridine (8.3 mg, 68 μmol), pyridine (0.14 mL, 1.7 mmol), and acetic anhydride (35 μL, 0.37 mmol) and stirred at 20° C. for 16 h. The reaction mixture was purified by preparative LCMS to give the desired product (95 mg, 70%). LCMS for C21H25N3O5Na (M+Na)+: m/z=422.0.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][S:46]([C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1)(=[O:48])=[O:47].NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:53][C:52]4[CH:54]=[CH:55][C:49]([S:46]([CH3:45])(=[O:47])=[O:48])=[CH:50][CH:51]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(S(C)(=O)=O)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-(methylsulfonyl)aniline as the aniline component. (15%, MS=534.2 (M+H))
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3[C:27]([O:29][CH2:30][CH2:31][CH2:32][O:33][P:34]([O:41]C(C)(C)C)([O:36]C(C)(C)C)=[O:35])=[O:28])=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].C(#N)C.FC(F)(F)C(O)=O.N>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3[C:27]([O:29][CH2:30][CH2:31][CH2:32][O:33][P:34]([OH:36])([OH:41])=[O:35])=[O:28])=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OP(=O)(OCCCOC(=O)n1ncc2c(NC(=O)N[C@@H]3CCc4cc(C(C)(C)C)ccc43)cccc21)OC(C)(C)C
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1ccc2c(c1)CC[C@H]2NC(=O)Nc1cccc2c1cnn2C(=O)OCCCOP(=O)(O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 81 %

Procedure:
To the product from Example 15D (2.12 g, 3.30 mmol) in a 250 ml round bottom flask was added acetonitrile (40 ml) and 0.1% trifluoroacetic acid in water (40 ml) and the reaction was stirred at room temperature for 4 days. Every 24 hours 0.5 ml of trifluoroacetic acid was added until day four. The reaction was concentrated to give a white powder in 81% yield. 1H NMR (CDCl3, 300 MHz); δ ppm 1.32 (s, 9H), 1.88-1.92 (m, 1H), 2.22-2.26 (m, 2H), 2.57-2.63 (m, 1H), 2.84-2.90 (m, 1H), 2.96-3.32 (m, 1H), 4.21 (m, 2H), 4.65 (t, J=6.11, 12.55Hz, 2H), 5.29 (t, J=7.46, 14.58 Hz, 1H), 7.28-7.31 (m, 3H), 7.52 (t, J=8.14, 16.28 Hz, 1H), 7.73 (d, J=7.45Hz, 1H), 7.83 (d, J=8.48Hz, 1H), 8.36 (s, 1H); MS (DCI/NH3) m/z 531.00; Calc for C25H31N4O7P: C, 54.45; H, 5.59; N, 9.92. Found: C, 54.84; H, 5.88; N, 9.92.
Reaction SMILES: Cl.[F:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[O:20].[CH2:25]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[N:35][C:36](Cl)=[C:37]([NH:42][CH:43]3[CH2:45][CH2:44]3)[N:38]=2)[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[N:35][C:36]([N:9]3[CH2:8][CH2:7][CH:6]([O:5][C:4]4[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=4[F:2])[CH2:11][CH2:10]3)=[C:37]([NH:42][CH:43]3[CH2:44][CH2:45]3)[N:38]=2)[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1.[C:19]([OH:20])([C:21]([F:24])([F:23])[F:22])=[O:18]
Reactant: COc1ccc(OC2CCNCC2)c(F)c1
Reactant: Clc1nc2c(nc1NC1CC1)CCN(Cc1ccccc1)C2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CC3)CCN(Cc3ccccc3)C4)CC2)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of 4-(2-fluoro-4-methoxyphenoxy)piperidine hydrochloride (73.2 mg, 0.280 mmol), 6-benzyl-3-chloro-N-cyclopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (100 mg, 0.233 mmol), sodium tert-butoxide (67.2 mg, 0.700 mmol), BINAP (21.8 mg, 0.035 mmol) and Pd2(dba)3 (10.7 mg, 0.012 mmol) in toluene (1.2 mL) was heated at 90° C. for 14 h. The mixture was directly purified by HPLC Method A to give the title compound as a TFA salt (114.2 mg, 97%) as a yellow foam. 1H NMR (400 MHz, methanol-d4) δ ppm 0.53-0.60 (m, 2H), 0.78-0.85 (m, 2H), 1.84-1.95 (m, 2H), 1.99-2.09 (m, 2H), 2.65-2.73 (m, 1H), 2.90-2.98 (m, 1H), 3.08-3.23 (m, 3H), 3.33-3.42 (m, 2H), 3.55-3.68 (m, 2H), 3.75 (s, 3H), 4.16-4.24 (m, 1H), 4.28-4.40 (m, 2H), 4.50-4.59 (m, 2H), 6.67 (s, 1H), 6.73 (dd, J=12.9, 3.0 Hz, 1H), 7.01-7.09 (m, 1H), 7.52-7.61 (m, 5H); ESI-MS m/z [M+H]+ 504.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[C:45]([Pb+3])[CH:44]=2)=[CH:39][CH:38]=1>ClCCl.Cl>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[C:45]([CH:6]3[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]3=[O:9])[CH:44]=2)=[CH:41][CH:42]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (described in U.S. Pat. No. 5,089,046A) (0.296 g, 1.74 mmol) and N,N-dimethylaminopyridine (1.06 g, 8.70 mmol) is added anhydrous chloroform (20 ml), followed by stirring at room temperature until dissolution. To this solution is added anhydrous toluene (5 ml), followed by 4′-chloro-4-methylbiphenyl-3-yllead triacetate (1.12 g, 1.91 mmol) in one portion and the reaction mixture heated at 80° C. for 1-2 hours. The mixture is allowed to cool to room temperature, then diluted with dichloromethane (150 ml) and dilute aqueous hydrochloric acid (30 ml), followed by stirring for 5 minutes and filtration through diatomaceous earth to remove inorganic residues (additional washing with solvents). All organic fractions are combined, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product is purified by column chromatography (100% hexane to hexane/ethyl acetate 5:1 ratio) then triturated with hexanes to afford 4-(4′-chloro-4-methylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.318 g) as a cream powder.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([OH:16])=O)=[CH:10][CH:9]=1)=[O:6])[CH:2]=[CH2:3].ClC(N(C)C)=C(C)C.[CH2:27]([O:30][C:31](=[O:67])[C:32]([N:52]1[C@H:55]([SH:56])[C@@H:54]([C@H:57]([O:59][C:60]([O:62][CH2:63][CH:64]=[CH2:65])=[O:61])[CH3:58])[C:53]1=[O:66])=[P:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:28]=[CH2:29].CN(C1C=CC=CN=1)C>C(Cl)Cl.[Ag].N1C=CC=CC=1>[CH2:27]([O:30][C:31](=[O:67])[C:32]([N:52]1[C@H:55]([S:56][C:14](=[O:16])[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])=[CH:18][CH:17]=2)[C@@H:54]([C@H:57]([O:59][C:60]([O:62][CH2:63][CH:64]=[CH2:65])=[O:61])[CH3:58])[C:53]1=[O:66])=[P:33]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH:28]=[CH2:29]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Reactant: C=CCOC(=O)Nc1ccc(OCC(=O)O)cc1
Agent: [Ag]
Agent: CC(C)=C(Cl)N(C)C
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)Nc1ccc(OCC(=O)S[C@@H]2[C@@H]([C@@H](C)OC(=O)OCC=C)C(=O)N2C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1.25 h

Procedure:
1 g of 4-(allyloxycarbonylamino)-phenoxyacetic acid is suspended in 2 ml of CH2Cl2 and 0.6 ml of 1-chloro-1-dimethylamino-2-methylprop-1-ene is added thereto. The mixture is stirred for 75 minutes and is then added dropwise, over a period of 5 minutes, to a solution of 1.74 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester, 50 mg of dimethylaminopyridine and 0.41 ml of pyridine in 30 ml of absolute methylene chloride. The title compound is obtained after working up analogously to Example 1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]12[CH2:19][CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=31)[C:11]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=1>ClCCl>[CH:7]1[C:6]2[C:5]3([CH2:4][CH2:3][CH:2]=[O:1])[CH2:19][CH:12]([C:13]4[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: OCCCC12CC(c3ccccc31)c1ccccc12
Solvent: ClCCl
Product: O=CCCC12CC(c3ccccc31)c1ccccc12

Procedure:
The starting β-(9,10-dihydro-9,10-methano-9-anthryl)propionaldehyde (M.P. 135°-140° C.) was prepared from 9-γ-hydroxypropyl-9,10-dihydro-9,10-methanoanthracene by treating with chromium trioxide-pyridine complex in dichloromethane for 5 minutes at room temperature.
Reaction SMILES: NC1C=CC=C(C(N)=O)C=1.[NH:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]([NH2:22])=[O:21])[C:14]=2[C:13](=[O:23])[C:12]1=[O:24].[CH:25]1[C:30]([NH:31][NH2:32])=[CH:29][CH:28]=[C:27]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:26]=1.Cl>>[NH:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]([NH2:22])=[O:21])[C:14]=2[C:13](=[O:23])[C:12]1=[O:24].[O:24]=[C:12]1[C:13](=[N:32][NH:31][C:30]2[CH:29]=[CH:28][C:27]([S:33](=[O:35])(=[O:34])[NH2:36])=[CH:26][CH:25]=2)[C:14]2[C:15]([C:20]([NH2:22])=[O:21])=[CH:16][CH:17]=[CH:18][C:19]=2[NH:11]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: NC(=O)c1cccc(N)c1
Agent: NC(=O)c1cccc2c1C(=O)C(=O)N2
Product: NC(=O)c1cccc2c1C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
1H-Indole-2,3-dione-4-carboxamide was prepared from aniline-3-carboxamide according to Procedure A in 3% yield: 1H NMR (DMSO-d6):δ 7.17 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), ), 7.56 (t, J=8.1 Hz, 1H), 8.02 (bs, 2H), 11.86 (bs, 1H); APCI+MS m/z 191 (M+1)−. Condensation of 1H-indole-2,3-dione-4-carboxamide with 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 31% yield: 1H NMR (DMSO-d6): δ 7.11 (d, J=8.3 Hz, 1H), 7.18 (s, 2H), 7.27 (d, J=8.8 Hz, 2H), 7.32 (d, J=7.0 Hz, 1H), 7.51 (d, J=7.4 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 8.0 (bs, 2H), 10.40 (s, 1H), 10.80 (s, 1H); APCI−MS m/z 359 (M)−. Anal. Calcd for C15H13N5O4S.0.12 H2O: C, 49.83, H, 3.69; N, 19.37; S, 8.86. Found C, 49.71, H, 3.71; N, 19.32; S, 8.84.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:6]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=[O:40]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([N:17]3[CH2:22][CH2:21][N:20]([CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][C:36]4=[O:40])[CH2:19][CH2:18]3)[C:6]=2[CH:23]=1
Reactant: Cc1ccc2c(c1)CC(N1CCNCC1)c1cc(Cl)ccc1S2
Reactant: O=C1CCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)CC(N1CCN(CCN3CCCC3=O)CC1)c1cc(Cl)ccc1S2

Procedure:
11 G. of 1-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)piperazine are heated together with 15.5 g. of potassium carbonate, 0.5 g. of sodium iodide, 11 g. of N-(beta-chloroethyl)-pyrrolidinone and 150 ml. of toluene under reflux conditions over a period of 12 hours. The reaction mixture is evaporated under reduced pressure. The residue is dispersed between water and ether and the ethereal phase is dried over sodium sulfate and evaporated, whereby there is obtained 1-{2-[4-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)1-piperazinyl]-ethyl}-2-pyrrolidinone, having a melting point of 153°-164°. The maleate melts at 179°-180°.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=1)[CH3:5])=[N+]=[N-].CP(C)C>O1CCCC1>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:22][CH:21]=[C:20]([CH3:23])[N:9]2[C:10](=[O:19])[C:11]=1[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cncc(F)c3)c(=O)n12
Agent: CP(C)C
Solvent: C1CCOC1
Product: Cc1csc2nc(C(C)N)c(-c3cncc(F)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of 7-(1-azidoethyl)-6-(5-fluoropyridin-3-yl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.020 g, 0.060 mmol) in tetrahydrofuran (3 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.079 mL, 0.079 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give the crude product (0.018 g), which was used directly in next step. LCMS calculated for C14H14FN4OS (M+H)+: m/z=305.1. Found: 305.0.
Reaction SMILES: CC1OC(C2NC3C(=CC=CC=3)N3[C:8]2=[C:9]2[N:31]([CH3:32])[C:29](=[O:30])[N:28]([CH3:33])[C:26](=[O:27])[C:10]2=C3C2C=CC=CC=2)=CC=1.S(OC)(OC)(=O)=O>>[CH3:32][N:31]1[C:9]([CH3:8])=[CH:10][C:26](=[O:27])[N:28]([CH3:33])[C:29]1=[O:30]
Reactant: Cc1ccc(C2Nc3ccccc3-n3c(-c4ccccc4)c4c(=O)n(C)c(=O)n(C)c4c32)o1
Solvent: COS(=O)(=O)OC
Product: Cc1cc(=O)n(C)c(=O)n1C
Yield: 98 %

Procedure:
Efforts were undertaken to improve methods for synthesizing PPQ-102 because the original synthesis method developed had low yield (see, e.g., Tradtrantip et al., J. Med. Chem. 52:6447-55 (2009); Int'l Patent Appl. Publication No. WO 2011/019737). As shown in Scheme 1,6-methyluracil 1 was exhaustively alkylated using dimethyl sulfate to give 1,3,6-trimethyluracil 2 in 98% yield. 1,3,6-Trimethyluracil 2 was subject to Friedel-Crafts acylation utilizing benzoyl chloride and anhydrous zinc chloride to give ketone 3a in 66% yield. Bromination of ketone 3a gave 4a in quantitative yield. At the first point of diversification, 4a was reacted with substituted 1,2-phenylenediamines (2 eq) to give pyrroles 5a-c in 97% (R2═H), 89% (R2═NO2), and 83% (R3=Me) yields. Pyrroles 5a-c were condensed with the appropriately substituted furfural or thiophene carbaldehyde using catalytic acid to give PPQ-(5-15, 23) with yields of 57-98%. PPQ-102 was obtained on a gram scale in 83% yield. Amide analogs were synthesized from PPQ-102 and acid halides or anhydrides to give PPQ-(1-3), in 73%, 80% and 79% yields, respectively. The nitrosamine PPQ-4 was synthesized from PPQ-102 and t-butyl nitrite in 79% yield.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6](=[O:8])[CH:7]=1.[C:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([OH:17])=[O:16].[O-]CC.[Na+].[Na].Cl>C(O)C>[O:8]=[C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:3][C:2]([CH:1]=[CH:22][C:21]2[CH:24]=[CH:25][C:18]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)=[CH:7]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Cc1cc(=O)cc(-c2ccccc2)o1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc(C=Cc2cc(=O)cc(-c3ccccc3)o2)cc1

Procedure:
2-Methyl-6-phenyl-4H-pyran-4-one (3.7 g) and 4-carboxybenzaldehyde (3.0 g) were added to a stirred solution of sodium ethoxide prepared by dissolving sodium (1.0 g) in ethanol (75 ml) and the mixture was heated under reflux for an hour, cooled and acidified with 2M hydrochloric acid (25 ml). The resulting solid was recrystallised from acetic acid and then from dimethylformamide-water to give the pale yellow title product (mp>300° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.[CH3:14][O-:15].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:3]([O:15][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2
Reactant: Cc1ccc2nc(Cl)c(N)nc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc2ccc(C)cc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To 3-amino-2-chloro-6-methylquinoxaline (550 mg, 2.84 mmol) dissolved in tetrahydrofuran (30 ml), 25 wt % sodium methoxide (6.14 g, 28.4 mmol) in methanol was added at room temperature and stirred further at room temperature for 60 minutes. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with dichloromethane and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with n-hexane:ethyl acetate (2:1) mixture and concentration gave 467 mg of the titled compound (yield, 87%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([Si:15]([CH3:33])([CH3:32])[O:16][C@H:17]1[CH2:26][CH2:25][CH2:24][C@@:23]2([CH3:27])[C@H:18]1[CH2:19][CH2:20][CH2:21][C@@H:22]2[C@H:28]([CH3:31])[CH2:29][OH:30])([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[C:11]([Si:15]([CH3:33])([CH3:32])[O:16][C@H:17]1[CH2:26][CH2:25][CH2:24][C@@:23]2([CH3:27])[C@H:18]1[CH2:19][CH2:20][CH2:21][C@@H:22]2[C@H:28]([CH3:31])[CH:29]=[O:30])([CH3:13])([CH3:14])[CH3:12]
Reactant: C[C@H](CO)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@H](C=O)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Swern reagent was prepared at -60° C. by adding slowly DMSO (0.899 ml, 11.5 mmol, dissolved in 2 ml of CH2Cl2) to oxalylchloride (0.503 ml, 5.85 mmol) in 10 ml of CH2Cl2. 15 Minutes later, (S)-2-[(1R,4aR,5S,8aR)-5-(tert-Butyl-dimethyl-silanyloxy)-8a-methyl-decahydro-naphthalen-1-yl]-propan-1-ol (1.81 g, 5.31 mmol), dissolved in 7 ml of CH2Cl2, was slowly added. After 1/2 h, NEt3 (5.18 ml, 37.2 mmol) was added and the temperature allowed to reach -25° C. The reaction was quenched by pouring onto crashed ice/NH4Cl, extracted twice with ether, washed with water and brine, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=97/3) yielded 1.583 g of (S)-2-[(1R,4aR,5S,8aR)-5-(tert-Butyl-dimethyl-silanyloxy)-8a-methyl-decahydro-naphthalen-1-yl]-propionaldehyde as isomerically pure, colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][C@@H:9]([C:21](=[O:33])[NH:22][C@H:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][C@@H:9]([C:21](=[O:33])[NH:22][C@H:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)[N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cc([N+](=O)[O-])ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cc(N)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reaction time: 1 h
Yield: 84 %

Procedure:
To a pressure flask containing 5% Pd/C (91 mg, 0.085 mg) was added a solution of (S)-tert-butyl 7-nitro-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.38 g, 0.85 mmol) in MeOH (8.5 mL). The resulting reaction mixture was stirred under 5 psi H2 for 1 h and then filtered through a pad of CELITE®, rinsing with EtOAc. The filtrate was concentrated in vacuo to give the title compound (301 mg, 84%) as a colorless oil. MS (ESI+) m/z 422.2 (M+H)+.