Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(O)=O)N=1)CC2)=O.[NH2:39][C:40]1[N:44](C(OC(C)(C)C)=O)[N:43]=[C:42]([C:52]2[CH:53]=[C:54]([CH:99]=[CH:100][CH:101]=2)[O:55][CH2:56][C:57]#[C:58][C:59]2[S:63][C:62]([N:64]3[CH2:73][CH2:72][C:71]4[C:66](=[C:67]([C:74](=[O:93])[N:75]([C:84]5[S:85][C:86]6[CH:92]=[CH:91][CH:90]=[CH:89][C:87]=6[N:88]=5)COCC[Si](C)(C)C)[CH:68]=[CH:69][CH:70]=4)[CH2:65]3)=[N:61][C:60]=2[C:94]([O:96]CC)=[O:95])[C:41]=1[C:102]#[N:103]>>[NH2:39][C:40]1[NH:44][N:43]=[C:42]([C:52]2[CH:53]=[C:54]([CH:99]=[CH:100][CH:101]=2)[O:55][CH2:56][C:57]#[C:58][C:59]2[S:63][C:62]([N:64]3[CH2:73][CH2:72][C:71]4[C:66](=[C:67]([C:74](=[O:93])[NH:75][C:84]5[S:85][C:86]6[CH:92]=[CH:91][CH:90]=[CH:89][C:87]=6[N:88]=5)[CH:68]=[CH:69][CH:70]=4)[CH2:65]3)=[N:61][C:60]=2[C:94]([OH:96])=[O:95])[C:41]=1[C:102]#[N:103]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCOc1cccc(-c2nn(C(=O)OC(C)(C)C)c(N)c2C#N)c1
Agent: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(-c3ccc(CO)cc3)s1)CC2
Product: N#Cc1c(-c2cccc(OCC#Cc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)c2)n[nH]c1N

Procedure:
Title compound 36 was prepared in a similar manner to the synthesis of compound 34 by substituting compound 34D with compound 36C in step 5 of Example 34: 1H NMR (DMSO-d6): δ 8.03 (d, J=7.93 Hz, 1H), 7.79 (d, J=7.93 Hz, 1H), 7.66-7.68 (m, 1H), 7.35-7.48 (m, 8H), 5.08 (s, 2H), 4.91 (s, 2H), 3.70-3.73 (m, 2H), 3.46-3.49 (m, 2H), 3.05-3.07 (m, 2H). MS (ESI(+)): m/z 670 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2].[CH:41](I)([CH3:43])[CH3:42]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH:41]([CH3:43])[CH3:42])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2]
Reactant: CC(C)I
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Product: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OC(C)C
Yield: 31 %

Procedure:
The same procedure as in Example 48 was repeated, using 335 mg (0.61 mmol) of Compound 47 obtained in Example 47, except that isopropyl iodide was used in place of methyl iodide, to give 112 mg (yield: 31%) of Compound 50 as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(Br)cc1Nc1ccccc1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
The product from Step 2 (7.55 g, 26.8 mmol) in THF (80 mL) and triethylamine (3.7 mL, 26.8 mmol) was treated with aniline (2.6 g, 27.9 mmol) and allowed to stir at rt until the reaction was judged complete by TLC. The solvent was removed in vacuo and the residue dissolved in ethyl acetate, washed (3×) with water and brinde, dried over Na2SO4 and concentrated in vacuo to afford the title compound (7.65 g, 97%). MS (ES+) m/e 294/296 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: CC(C)CN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CC(C)CN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-isobutyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide to yield a white solid (25%). LCMS: m/z=523.54 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.54 (m, 2H), 7.28 (m, 2H), 7.09 (d, 1H, J=7.3 Hz), 6.32 (s, 2H), 5.87 (s, 1H), 5.81 (s, 1H), 4.33 (m, 1H), 3.08 (s, 1H), 2.90 (s, 1H), 2.51 (d, 1H, J=8.1 Hz), 2.36 (m, 4H), 2.03 (m, 3H), 1.63 (d, 1H, J=8.6 Hz), 1.27 (m, 1H), 1.00 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[H-].[Na+].[CH3:18]N(C)C=O.CI>O>[CH3:18][N:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[NH:5][C:4]2=[CH:3][S:2][CH:1]=[C:10]2[C:9]1=[O:11]
Reactant: CN(C)C=O
Reactant: O=C1Nc2ccccc2Nc2cscc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1C(=O)c2cscc2Nc2ccccc21
Reaction time: 2.5 h

Procedure:
To a stirred mixture of 0.84 g. of 4,9-dihydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and 0.18 g. of 55% sodium hydride-mineral oil dispersion in 25 ml. of dimethylformamide is added 0.3 ml. of methyl iodide. The reaction mixture is stirred for 2.5 hours, cooled, diluted with water and filtered. The solid product is recrystallized from methanol-water to give pale yellow crystals, m.p. 195°-198°C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:16]([O:7][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1H-pyrrole-2-carboxylic acid (1.11 g, 10 mmol) in DMF (15 mL) is added potassium carbonate (2.07 g, 15 mmol) and (bromomethyl)benzene (1.80 g, 10.50 mmol). After stirring the mixture at room temperature for 18 hours, water is added and the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate=5:1) to give 1H-pyrrole-2-carboxylic acid benzylester.
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][N:32]=4)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:36])([F:35])[F:34])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>CO.CO.C(Cl)Cl>[CH3:37][N:3]1[CH2:4][CH2:5][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][N:32]=4)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:36])([F:34])[F:35])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)c1ccnc(CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cc(C(N)=O)ccn4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
Formaldehyde solution (37% aq; 24 μL, 0.30 mmol) was added to a solution of 2-(2-(2-((4-(Piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)isonicotinamide (I131) (28 mg, 60 μmol) in dry MeOH (2 mL). Sodium triacetoxyborohydride (63 mg, 0.30 mmol) was added and the resulting mixture stirred at room temperature for 2 hours under nitrogen. Ethyl acetate was added and the resulting solution adsorbed onto silica gel. Chromatography (SiO2, 0-50% MeOH/DCM) gave the title compound (34) (14 mg, 49%) as a colourless solid; 1H NMR (400 MHz, d4-MeOD) δ 8.58 (d, J=4.9 Hz, 1H), 8.51 (s, 1H), 7.73 (s, 1H), 7.61 (dd, J=5.2, 1.6 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.6 Hz, 2H), 3.51-3.31 (m, 4H), 2.99 (d, J=11.7 Hz, 2H), 2.56-2.44 (m, 1H), 2.32 (s, 3H), 2.15 (d, J=2.8 Hz, 2H), 1.87-1.70 (m, 4H). LCMS Method C: rt 4.50 min; m/z 485.1 [M+1]+, 483.1 [M−1]−.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:10]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26](=[O:28])[CH3:27])=[CH:20][CH:19]=3)[CH:12]=[C:13]3[CH:17]=[CH:16][S:15][C:14]=23)[CH2:5][CH2:4]1)[CH3:2].[CH3:29][Mg]Br.CCOCC.[Cl-:37].[NH4+].C(OCC)(=O)C>O1CCCC1>[ClH:37].[ClH:37].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:10]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])([CH3:29])[CH3:27])=[CH:20][CH:19]=3)[CH:12]=[C:13]3[CH:17]=[CH:16][S:15][C:14]=23)[CH2:5][CH2:4]1)[CH3:2]
Reactant: C[Mg]Br
Reactant: CCN1CCN(c2nc(-c3ccc(CCC(C)=O)cc3)cc3ccsc23)CC1
Reactant: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(CCC(C)(C)O)cc3)cc3ccsc23)CC1
Product: Cl

Procedure:
The resulting 7-(4-ethylpiperazin-1-yl)-5-[4-(3-oxobutyl)phenyl]thieno[2,3-c]pyridine (0.23 g) was dissolved in tetrahydrofuran (10 ml), and the resulting mixture was stirred under ice-cooling. To the resulting mixture was added 3.0M methylmagnesium bromide/ether solution (0.39 ml), and the mixture was further stirred for 3 hr. Then, 3.0M methylmagnesium bromide/ether solution (0.39 ml) was further added thereto, and the mixture was further stirred for 4.5 hr. Then, an aqueous solution of saturated ammonium chloride and ethyl acetate were added to the mixture, and the mixture was stirred. The organic layer was separated, and then it was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate/n-hexane system), to give 0.10 g of the free compound of the title compound as a colorless viscous oil.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]([CH3:21])[CH2:19][OH:20])[CH:12]=[CH:11]2>>[S:1]([O:20][CH2:19][CH:18]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH3:6])[CH:9]=2)[CH:14]=1)[CH3:21])(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: COc1ccc2cc(C(C)CO)ccc2c1
Product: COc1ccc2cc(C(C)COS(N)(=O)=O)ccc2c1
Yield: 21 %

Procedure:
The title compound was prepared by the procedure of Example 33 from sulfamoyl chloride and 2-(6-methoxy-2-naphthyl)propanol as white solid, mp 112°-115° C., in 21% yield.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]([NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26]([O:28]C(C)(C)C)=[O:27])[CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[F:34][C:2]([F:1])([F:33])[CH:3]([NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1
Reactant: CC(C)(C)OC(=O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 2({2,2,2-trifluoro-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1-benzofuran-6-carboxylate (450 mg, 1.04 mmol) in dichloromethane (4.5 ml) was admixed at 0° C. with trifluoroacetic acid (0.46 ml, 6.0 mmol) and stirred at room temperature overnight. Subsequently, the reaction mixture was washed with water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was filtered through silica gel, the filtercake was rinsed with ethyl acetate and methanol, and the filtrate was concentrated.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:5]=2[CH:6]=1.CS[C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17].C(N(CC)CC)C.[NH2:28][CH:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[N:31]([CH2:40][C:41]([N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[O:42])[C:30]1=[O:48]>C(O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([NH:11][C:14]([NH:28][CH:29]3[CH2:35][CH2:34][C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]([CH2:40][C:41]([N:43]4[CH2:44][CH2:45][CH2:46][CH2:47]4)=[O:42])[C:30]3=[O:48])=[CH:15][N+:16]([O-:18])=[O:17])=[CH:7][C:5]=2[CH:6]=1
Reactant: NC1CCc2ccccc2N(CC(=O)N2CCCC2)C1=O
Reactant: Cc1cc2cc(N)ccc2o1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc2cc(NC(=C[N+](=O)[O-])NC3CCc4ccccc4N(CC(=O)N4CCCC4)C3=O)ccc2o1
Temperature: 80 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
A solution of 2-methyl-5-benzofuranamine (0.24 mmol), 1,1-bis(methylthio)-2-nitroethylene (40 mg, 0.24 mmol) and triethylamine (0.035 mL, 0.25 mmol) in ethanol (0.35 mL) was stirred at 80° C. for 2 h. To the mixture was added 1-[(3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl)acetyl]pyrrolidine (70 mg, 0.24 mmol) and the resulting reaction was stirred at 80° C. overnight. The reaction mixture was purified by column chromatography (silica, 3% methanol/ethyl acetate) to provide the title compound (29 mg, 24% yield): MS (ESI, pos. ion spectrum) m/z 504; HPLC (method A) tR 3.67 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH2:11])[CH:3]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[CH3:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[NH2:11]
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(F)cc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.), stirred solution of 4-fluoro-2-aminobenzoic acid (2.68 g; 17.3 mmol) in dry tetrahydrofuran (60 mL) and MeOH (10 mL) was added a solution of trimethylsilyldiazomethane in hexanes (12 mL of 2.0 N; 24 mmol) via syringe over 20 minutes under nitrogen atmosphere. The resulting solution was allowed to warm to room temperature and stirred for 2 hours then concentrated in vacuo to provide the ester a light yellow solid (˜100%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:22][CH:23]2[CH2:28][CH2:27][C:26](=O)[NH:25][CH2:24]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.P(Cl)(Cl)(Cl)=O>O1CCOCC1.O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:22][CH:23]2[CH2:24][N:25]3[C:26](=[N:1][C:2]4[C:3]([C:4]3=[O:6])=[CH:7][CH:8]=[C:9]([Br:11])[CH:10]=4)[CH2:27][CH2:28]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: O=C1CCC(OS(=O)(=O)c2ccc(Br)cc2)CN1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1c2ccc(Br)cc2nc2n1CC(OS(=O)(=O)c1ccc(Br)cc1)CC2
Temperature: 25 °C

Procedure:
A solution of 2-amino-4-bromobenzoic acid (1.4 g, 6.6 mmol, 1.1 equiv), 6-oxopiperidin-3-yl 4-bromobenzenesulfonate (2 g, 6.0 mmol, 1 equiv), and phosphoryl trichloride (4 mL) in 1,4-dioxane (100 mL) was stirred at 80° C. for two hours. After it was cooled to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:15]([C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)[NH2:16]>CO.C(O)(=O)C>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[NH:15][N:16]=[C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(c1ccccn1)C1CCCCC1
Reactant: NNc1nc2ccccc2s1
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(C(=NNc2nc3ccccc3s2)C2CCCCC2)nc1

Procedure:
A mixture of cyclohexyl-(2-pyridyl)-methanone (0.77 g, 4.05 mmol) and 2-hydrazinobenzothiazole (0.60 g, 4.02 mmol) in 15 ml of methanol is refluxed for 15 hours after the addition of 5 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: petroleum ether:ethyl acetate (3:7)). The reaction mixture is stored over night in the refrigerator at approximately 5° C. The precipitate is filtered and recrystallized from a mixture of ethanol and water. Yield: 1.09 g (80% of theory).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([S:14][CH2:15][C:16]([OH:33])([CH3:32])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=2)=[O:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:39].[OH2:49]>ClCCl.[Cl-].[Na+].O>[CH2:1]([C:8]1[CH:9]=[C:10]([S:14]([CH2:15][C:16]([OH:33])([CH3:32])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:21]=2)=[O:18])(=[O:39])=[O:49])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(CSc1cccc(Cc2ccccc2)c1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)(CS(=O)(=O)c1cccc(Cc2ccccc2)c1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
3-(3-benzylphenylthio)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide (15 mg, 0.033 mmol) was dissolved in dichloromethane (0.05 mL) and cooled to −78° C. 30% hydrogen peroxide (5.7 μL, 0.2 mmol) was added followed by the slow addition of trifluoroacetic anhydride (23 μL, 0.17 mmol). The reaction was stirred at room temperature for 16 h. The reaction was diluted with dichloromethane. Cold water and brine were added, and the reaction was stirred for 20 minutes. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography (hexane:EtOAc 50:50) yielded 11 mg of desired product. Production of PLM3 was confirmed by 1-H NMR, 13-C NMR, and mass spectral analysis.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Br>>[O:27]1[CH2:26][CH:25]1[CH2:23][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1ccccc1O)c1ccccc1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(Nc1ccccc1OCC1CO1)c1ccccc1

Procedure:
To a stirred solution of N-(2-Hydroxy-phenyl)-benzamide (0.81 g, 3.80 mmol), and cesium carbonate (1.61 g, 4.94 mmol) in acetontrile was added epibromohydrin (0.63 ml, 7.60 mmol). After 4 hours the reaction mixture was partitioned between dichloromethane and water. After evaporation of the organic solvent the residue was crystallised from petroleum ether and diethyl ether yielding (0.741 g, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:26]=2)=[N:10]1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][C@H:33]1[C:38]([OH:40])=[O:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[N:26]=2)[NH:12][C:13]([CH2:20][N:32]2[CH2:37][CH2:36][O:35][CH2:34][C@H:33]2[C:38]([OH:40])=[O:39])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc(CC(=O)OC)cs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)[C@@H]1COCCN1
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nc(CC(=O)OC)cs2)=NC1c1ccc(F)cc1Br
Yield: 60 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(4-(2-methoxy-2-oxoethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.15 g, 2 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.39 g, 3 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.75 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([C:19]#[N:20])([CH3:18])[CH3:17])[CH:11]=2)=[CH:4][C:3]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][N:24]=1.[Cl-].[Ca+2].[Cl-].O>C(O)C>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:21])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([C:19]#[N:20])([CH3:17])[CH3:18])[CH:11]=3)[CH:6]=[CH:7][C:2]=2[Cl:1])=[N:24][CH:25]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc([N+](=O)[O-])cn3)c2)c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc(N)cn3)c2)c1
Temperature: 90 °C
Yield: 62.3 %

Procedure:
A suspension of N-{4-chloro-3-[(5-nitropyridin-2--yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (2.5 g, 5.72 mmol), calcium chloride (2.00 g, 17.2 mmol) and reduced iron (1.43 g, 25.7 mmol) in ethanol (35 mL)/water (5 mL) was stirred with heating at 90° C. for 4 hr. After the reaction mixture was cooled to room temperature, the insoluble material was filtered off through a pad filled with celite, and washed with ethyl acetate. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (100 mL), washed with water (50 mL×2), 5% aqueous sodium hydrogen carbonate solution (50 mL×2) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (1.45 g, 62%) as a beige amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.Cl>O1CCCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([B:18]([OH:21])[OH:19])=[CH:11][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COc1ccc2ccccc2c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cc2ccccc2cc1B(O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
Under a nitrogen atmosphere, 15.0 g (94.9 mmol) of 2-methoxynaphthalene was dissolved in tetrahydrofuran (300 ml), and the solution was cooled to 0° C. After that, 238 mL (1.6-mol/L solution, 190 mmol) of normal butyllithium were slowly dropped to the solution. After the dropping, the mixture was stirred at 0° C. for 2 hours. After that, the mixture was cooled to −10° C., and 33 mL (340 mmol) of trimethyl borate was dropped over 10 minutes to the mixture. The resultant was heated to room temperature, and was stirred overnight. After that, 0.2N hydrochloric acid was added to the resultant to stop the reaction. Chloroform was added to the resultant to separate an organic layer, and the layer was washed with a saturated aqueous solution of ammonium chloride once and with water four times. After that, the solvent was removed by distillation, and heptane and toluene were added to the resultant residue to purify the residue by recrystallization, whereby 4.81 g of Intermediate Compound 6 were obtained.