Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([O:26][CH3:27])[CH:14]=1.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[C:36]([CH2:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:37]=1)[NH:34][CH:33]=[CH:32]2.[Cl-].[NH4+]>ClCCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:32]2[C:31]3[C:35](=[C:36]([CH2:38][S:39]([CH3:42])(=[O:40])=[O:41])[CH:37]=[C:29]([F:28])[CH:30]=3)[NH:34][CH:33]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([O:26][CH3:27])[CH:14]=1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: COc1cc(Cl)ccc1C(O)C1CC1C#N
Agent: [Cl-]
Agent: [In+3]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1cc(Cl)ccc1C(c1c[nH]c2c(CS(C)(=O)=O)cc(F)cc12)C1CC1C#N

Procedure:
104 mg (0.47 mmol) of indium(III) chloride and 0.05 ml (0.70 mmol) of trifluoroacetic acid were added to 93.0 mg (0.39 mmol) of the compound from Example 163A and 121 mg (0.47 mmol) of the compound from Example 87A with a purity of 88% under argon in 5 ml of 1,2-dichloroethane, and the mixture was heated under reflux for 2 h. Addition of the reaction mixture to saturated aqueous ammonium chloride solution was followed by extraction with dichloromethane, drying over magnesium sulfate, filtration and concentration. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 35.0 mg (20% of theory) of diastereomer 1 and 31.3 mg (18% of theory) of diastereomer 2 of the title compound.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[N:16]=[C:17]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[C:18]([C:23]([NH2:25])=[O:24])=[N:19][C:20]=1[CH2:21][CH3:22])C1C=CC=CC=1>[Pd].C(O)(=O)C>[CH2:21]([C:20]1[N:19]=[C:18]([C:23]([NH2:25])=[O:24])[C:17]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[N:16][C:15]=1[O:14][CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[CH3:22]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1OC[C@H]1CCCN1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1OC[C@H]1CCCN1
Reaction time: 6 h
Yield: 88.9 %

Procedure:
To a mixture of 5-{[(2R)-1-benzylpyrrolidin-2-yl]methoxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (182 mg), and acetic acid (3 mL) was added 10% palladium-supported carbon (53% wet product) (63 mg), followed by stirring for 6 hours under a hydrogen gas atmosphere (4 atm). The reactant was filtered through celite, then the mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with a mixed solvent of chloroform:methanol=8:2. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type: eluent; chloroform:methanol=98:2) to obtain 6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-[(2R)-pyrrolidin-2-ylmethoxy]pyrazine-2-carboxamide (138 mg) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH:8]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:7]2=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>CN(C)C=O>[C:27]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH:8]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([CH3:3])[CH:5]=2)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(C(=O)OCc1ccccc1)CCC3
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2C(=O)c2ccccc2)CCCC1C(=O)OCc1ccccc1

Procedure:
Following a procedure similar to that of Example 35B but using 0.84 g. sodium hydride, 50 ml. of dry dimethylformamide, 9.1 g. of benzyl 6-methyl-1,2,3,4-tetrahydrocarbazole-4-carboxylate, and 4.4 g. of benzoyl chloride, but eliminating the 1% aqueous hydrochloric acid wash subsequent to the bicarbonate wash, there was obtained 8.5 g. of the title compound which was purified by suspension in hot isopropyl alcohol, filtration, followed by suspension in, and filtration from, ether; m.p. 119°-121°C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13](S(C)=O)=[N:14][N:15]=3)[CH:9]=2)[N:4]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:3]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>O1CCOCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([NH:36][CH2:35][C:34]4[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=4)=[N:14][N:15]=3)[CH:9]=2)[N:4]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=2)(=[O:21])=[O:20])[CH:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(S(C)=O)s4)ccc32)cc1
Solvent: C1COCCO1
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Temperature: 100 °C
Yield: 52.4 %

Procedure:
To a mixture of 2-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(methylsulfinyl)-1,3,4-thiadiazole (423 mg, 0.757 mmol) in dioxane (3.0 mL) was added 4-methoxybenzylamine (0.294 mL, 2.268 mmol) at RT. The reaction was heated at 100° C. for 24 h. The solvent was removed and the residue was sonicated in MeOH and filtered. The filtrate was concentrated and the residue was purified with flash chromatography (eluting with 0-50% EtOAc in DCM) to give 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (245 mg, 0.397 mmol, 47%). MS (ESI, pos. ion) m/z: 617 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (t, J=5.67 Hz, 1H), 8.16 (s, 1H), 8.03 (d, J=8.61 Hz, 1H), 7.94 (d, J=8.41 Hz, 2H), 7.79 (dd, J=8.71, 1.66 Hz, 1H), 7.62 (d, J=1.56 Hz, 1H), 7.42 (d, J=8.41 Hz, 2H), 7.32 (d, J=8.61 Hz, 2H), 6.92 (d, J=8.61 Hz, 2H), 4.46 (d, J=5.67 Hz, 2H), 3.73 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:17]=[CH:16][C:15]2[N:14]([CH3:18])[C:13](=[O:19])[C@@H:12]([CH2:20][CH3:21])[N:11]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:10]=2[N:9]=1.Cl[CH2:28][O:29][C:30](=O)[O-:31].O>N1C=CC=CC=1>[CH:22]1([N:11]2[C:10]3[N:9]=[C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[NH:1][C:30](=[O:31])[O:29][CH3:28])[N:17]=[CH:16][C:15]=3[N:14]([CH3:18])[C:13](=[O:19])[C@H:12]2[CH2:20][CH3:21])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C([O-])OCCl
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3N)nc2N1C1CCCC1
Solvent: O
Solvent: c1ccncc1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3NC(=O)OC)nc2N1C1CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91, 1 eq) and chloromethylcarbonate (10 eq) in dry pyridine under Ar was stirred at 80° C. overnight. The mixture was cooled to rt and water was added, then extracted with EtOAc. The organic layer was dried with Na2SO4, then concentrated and the residue was purified by a silica gel column to give the title compound. LCMS (0.05% TFA): 411.1 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 12.22 (s, 1H), 9.56 (s, 1H), 8.43 (d, 1H, J=5 Hz), 8.30 (s, 1H), 8.26 (d, 1H, J=5 Hz), 4.48 (m, 2H), 3.79 (s, 3H), 3.39 (s, 3H), 2.12-1.69 (m, 10H), 0.82 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH3:6][C:7]([C:10]1[CH:15]=[C:14]([CH:16]([NH:23][OH:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:11]=1[OH:29])([CH3:9])[CH3:8]>C1(C)C=CC=CC=1>[CH3:26][C:25]([C:12]1[CH:13]=[C:14]([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:23]([OH:24])[C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH:15]=[C:10]([C:7]([CH3:6])([CH3:8])[CH3:9])[C:11]=1[OH:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)c1cc(C(NO)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Product: CCNC(=O)N(O)C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl isocyanate (0.404 g, 0.0057 mole) is added to a solution of 1.64 g (0.005 mole) of 2,6-bis(1,1-dimethylethyl)-4-[(hydroxyamino) phenylmethyl]phenol in 50 mL toluene. After stirring at room temperature for 30 minutes the reaction mixture is concentrated to half its volume (rotary evaporator) and diluted with n-hexane. The solid is filtered off, washed with n-hexane, and recrystallized from Et2O-cyclohexane to give white crystals, 1.35 g (68%), m.p. 158°-159.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2C(OC(C)(C)C)=O)=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[ClH:24]>O1CCOCC1>[ClH:24].[CH3:8][C:6]1[CH:5]=[C:4]([NH:9][C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[O:11])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(NC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C)cc(NC(=O)[C@@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude (S)-tert-butyl 2-((3,5-dimethylphenyl)carbamoyl)pyrrolidine-1-carboxylate (17, 4.07 g; 10.7 mmol) is dissolved in dioxane (15 ml) followed by the addition of 4M HCl in dioxane (60 ml) Stirring at rt is continued for 30 minutes. The solvent is evaporated under reduced pressure. The residue is taken up into ether which caused the formation of a white precipitate which was filtered off, washed with ether and dried at high vacuum to give 3.299 g (quantitative yield) of (S)—N-(3,5-dimethylphenyl)pyrrolidine-2-carboxamide hydrochloride (18) as a white solid. LC-MS: tR=0.51 min; [M+H]+=219.07.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:8][C:6]1[CH:7]=[C:2]([O:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=[C:4]([CH3:12])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1c(C)cc(Cl)cc1C
Reactant: Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(=O)c1c(C)cc(Oc2ccccc2)cc1C
Temperature: 100 °C
Yield: 68 %

Procedure:
To a solution of 1-(4-chloro-2,6-dimethylphenyl)ethanone (4.50 g, 24.6 mmol), K3PO4 (10.5 g, 49.3 mmol), and phenol (2.78 g, 29.5 mmol) in toluene (49.3 mL) was added 2-(di-tert-butylphosphino)biphenyl (221 mg, 0.74 mmol) and Pd(OAc)2 (233 mg, 1.04 mmol). The reaction was heated at 100° C. for 2.0 h under N2. The solution was cooled to room temperature and filtered through a small pad of diatomaceous earth. The cake was washed with ethyl acetate (50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(2,6-dimethyl-4-phenoxyphenyl)ethanone as a yellow oil in 68% yield: 1H NMR (500 MHz, CDCl3) δ 7.35 (t, J=8.0 Hz, 2 H), 7.12 (t, J=7.5 Hz, 1 H), 7.00 (d, J=7.5 Hz, 2 H), 6.65 (s, 2 H), 2.48 (s, 3H), 2.22 (s, 6 H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[C:12]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:13][C:14]2[O:18][C:17](CCCCCCCC)=[CH:16][C:15]=2[C:27]=1[C:28]([CH3:31])([CH3:30])[CH3:29])(=O)C.O.Cl>O1CCCC1>[C:28]([C:27]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH:13]=[C:12]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:11]=1[OH:10])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCCCCCCCc1cc2c(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)cc2o1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc2occc2c(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 132.5 %

Procedure:
Lithium aluminum hydride (0.26 g) was suspended in tetrahydrofuran (50 ml) under a nitrogen atmosphere and a solution of 5-acetoxy-4,6-di-tert-butyl-2-octylbenzofuran (2.7 g) in tetrahydrofuran (20 ml) was added to the suspension under cooling with ice. After heating under reflux for 3 h, the mixture was cooled to room temperature and water was added dropwise. After adding 10% aqueous HCl (50 ml), the mixture was subjected to extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 4,6-di-tert-butyl-5-hydroxybenzofuran [2.2 g (yield, 92%)] as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([CH:48]=[CH:49][CH:50]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:45]=[CH:46][CH:47]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:30])[CH:11]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-morpholinophenyl)carbamoyl)benzylthio)propanoate (100 mg, 0.14 mmol, 1.00 equiv) in dichloromethane (5 mL), and trifluoroacetic acid (0.1 mL). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 14 mg (15%) of a yellow solid. 1H-NMR (300 MHz, CDCl3, ppm): δ 13.55 (s, 1H), 9.09 (s, 1H), 8.96-8.78 (m, 2H), 8.72 (s, 1H), 8.65 (s, 1H), 8.25-8.09 (m, 3H), 8.05-7.90 (m, 8H), 4.73 (d, J=5.4 Hz, 2H), 4.13 (s, 4H), 3.82 (s, 2H), 3.47 (s, 4H), 2.75-2.57 (m, 4H). MS (ES, m/z): 679 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
A mixture of 2-chloro-5-methylbenzoic acid (4.0 g, 23.4 mmol) in methanol (50 mL) and a few drops of concentrated sulfuric acid were stirred at reflux for 5 hours. After cooling to room temperature, methanol was evaporated. The residue was dissolved in ethyl acetate (50 mL). The solution was extracted with saturated NaHCO3 (3×50 mL). The organic layer was dried over MgSO4, filtered, evaporated, and dried in vacuo, affording methyl 2-chloro-5-methylbenzoate (3.07 g, 71% yield). The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1C2C(=CC=CC=2)CCC1.[O:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([N:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:21][CH2:22][CH2:23]1)=[O:6]
Reactant: O=C(O)c1ccncc1Br
Reactant: c1ccc2c(c1)NCCO2
Agent: c1ccc2c(c1)CCCN2
Product: O=C(c1ccncc1Br)N1CCOc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 6, Step 1, replacing 2-chloro-nicotinic acid with 3-bromo-isonicotinic acid [CAS RN 13959-02-9]) and 1,2,3,4-tetrahydro-quinoline with 3,4-dihydro-2H-benzo[1,4]oxazine ([CAS RN 5735-53-5]). MS (ISP): 319.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[N:43]=[C:44]=[O:45]>CCCCCC>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[NH:43][C:44](=[O:45])[N:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][S:18][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCCCCCCNCCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Solvent: CCCCCC
Product: CCCCCCCN(CCCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)Nc1ccc(F)cc1F
Yield: 28 %

Procedure:
Part C. To a solution of 8-(4,5-diphenyl-1H-imidazol-2-ylthio)-N-heptyl-1-octanamine (0.5 g, 0.001 mol) in hexane (25 mL) was added, dropwise, a solution of 2,4-difluorophenylisocyanate (0.15 mL, 0.194 g, 0.00125 mol) in hexane (10 mL), and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under vacuum and the residue was chromatographed using 8:2 hexane-ethyl acetate to give a solid which was triturated with cold ethyl acetate and then hexane to give the title compound (0.18 g, 0.00028 mol) as a white solid, mp 89°-91°. 1H NMR (DMSO-d6) δ12.5(s,1H), 7.9(s,1H), 7.5-7.1(m,10H), 3.3-3.1(m,5H), 1.8-1.2(m,17H), 0.9(t,3H,J=8Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13](O)=[O:14])=[C:11]([Cl:16])[N:10]=[C:9]([S:17][CH3:18])[N:8]=1.S(Cl)([Cl:26])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([Cl:26])=[O:14])=[C:11]([Cl:16])[N:10]=[C:9]([S:17][CH3:18])[N:8]=1
Reactant: COc1ccc(CNc2nc(SC)nc(Cl)c2C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Product: COc1ccc(CNc2nc(SC)nc(Cl)c2C(=O)Cl)cc1Cl
Temperature: 75 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-6-chloro-2-methylthiopyrimidine 10.50 g and thionyl chloride 25 ml is stirred for 20 minutes at 75° C. After reaction thionyl chloride is distilled off and the solvent is removed by azeotrope with methylene chloride to give 4-(3-chloro-4-methoxybenzylamino)-5-chloroformyl-6-chloro-2-methylthiopyrimidine.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br.[NH2:17][C:18]1[N:27]=[C:26]([NH2:28])[C:25]2[C:20](=[N:21][CH:22]=[C:23]([CH2:29]Br)[N:24]=2)[N:19]=1.CO>C1COCC1>[NH2:17][C:18]1[N:27]=[C:26]([NH2:28])[C:25]2[C:20](=[N:21][CH:22]=[C:23]([CH2:29][N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:24]=2)[N:19]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Reaction time: 0.17 h

Procedure:
Powdered NaH (50 mg, 2.1 mmol) is added to a stirred solution of diphenylamine (1.3 g, 0.77 mmol) in dry THF (10 mL) at 0° C. under N2. After 10 min, 2,4-diamino-6-bromomethylpteridine hydrobromide (100 mg, 0.3 mmol) is added and the reaction mixture is allowed to come to room temperature and left to stir for 2 days. The excess NaH is decomposed with MeOH (1 mL) and the mixture is concentrated to dryness by rotary evaporation. Flash chromatography on silica gel with 95:5 CHCl3-MeOH as the eluent affords the product, N-(2,4-diaminopteridin-6-yl)methyl-N,N-diphenylamine, as a bright-yellow powder (56 mg, 54% yield); mp >250° C. dec.; MS (FAB) m/z (M+1)=344; IR (KBr) v 3450, 3340, 3170, 1630, 1590, 1550, 1490, 1450, 1360, 1220 cm−1; 1H NMR(d6-DMSO) δ 5.10 (s, 2H, CH2), 6.70 (m, 10H, aromatic), 8.60 (s, 1H, C7-H. Anal. Calcd for C19H17N7.0.8H2O: C, 63.73; H, 5.23; N, 27.40. Found: C, 64.15; H, 4.85; N, 27.07.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:21])[CH2:17][C:18](=O)[CH3:19])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[NH3:24]>CO>[NH2:24]/[C:18](/[CH3:19])=[CH:17]\[C:16]([NH:15][C:5]1[CH:6]=[CH:7][C:8]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=1)=[O:21]
Reactant: N
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Solvent: CO
Product: C/C(N)=C/C(=O)Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(3-trifluoromethyl-4-morpholinophenyl)-3-oxobutanamide (4.0 g, 12.1 mmol), MeOH (20 mL) and ammonia (20 mL) was stirred at rt overnight. The mixture was then concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:11][CH2:10][CH2:9][S:8][C:6]1[N:7]=[C:2]([NH2:1])[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCSc1ccc([N+](=O)[O-])c(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCSc1ccc([N+](=O)[O-])c(N)n1

Procedure:
6-[(2-Aminoethyl)thio]-3-nitropyridine-2-amine trifluoroacetate (Example 46A) is prepared in analogy to Example 40A from tert-butyl {2-[(6-amino-5-nitropyridin-2-yl)thio]ethyl}carbamate (Example 43A) (380 mg, 1.2 mmol) and trifluoroacetic acid (1.9 ml, 24 mmol) in dichloromethane (20 ml). 400 mg of the product are obtained.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.[CH:13]([B-](F)(F)F)=[CH2:14].[K+]>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:10][C:6]1[C:5]([O:11][CH3:12])=[CH:4][CH:3]=[C:2]([CH:13]=[CH2:14])[C:7]=1[CH:8]=[O:9]
Reactant: COc1ccc(Br)c(C=O)c1F
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCCO
Product: C=Cc1ccc(OC)c(F)c1C=O
Temperature: 25 °C

Procedure:
To a stirred solution of 6-bromo-2-fluoro-3-methoxybenzaldehyde (13 g, 56 mmol) in nPrOH (200 mL) were added potassium vinyltrifluoroborate (7.9 g, 59 mmol), PdCl2(dppf) (0.91 g, 1.1 mmol), and TEA (7.8 mL, 56 mmol). The reaction mixture was purged with N2 for 10 min, heated to reflux for 3 h, cooled to room temperature, treated with water, and concentrated. The residue was extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na2SO4), concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.53 (s, 1H); 7.43 (dd, 1H); 7.31 (d, 1H); 7.16 (t, 1H); 5.60 (d, 1H); 5.36 (d, 1H); 3.95 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[OH-].[Na+].Cl>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH:10]=[CH:17][C:16]1[CH:19]=[CH:20][C:13]([OH:12])=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)c1c(O)cccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(O)cc1)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of 7.6 grams (0.05 mole) of 2',6'-dihydroxyacetophenone and 6.1 gram (0.05 mole) p-hydroxybenzaldehyde in ethanol was added 100 ml. of 60% aqueous sodium hydroxide. The mixture was stirred at room temperature for 18 hours and then acidified with 6 N hydrochloric acid. The resulting orange solid was collected by filtration and washed with water. The solid was chromatographed on silica gel (200 g., 2.25 l., 20% acetone-Skellysolve "B") and 150 ml. fractions taken. Fractions 6-12 were combined and crystallized from methanol-methylene chloride giving fine orange needles, 28 g., m.p. 190°-192° C., resolidified and melted 210°-212° C., 22% yield).