Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCC)=[O:23])[C:4]1=[O:27])[CH3:2].[NH2:28][CH:29]([CH3:32])[CH2:30][OH:31]>>[CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:28][CH:29]([CH3:32])[CH2:30][OH:31])=[O:23])[C:4]1=[O:27])[CH3:2]
Reactant: CC(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC)c1=O
Product: CCn1c(=O)c(C(=O)NC(C)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 64.9 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.081 mmol) and 2-amino-1-propanol (0.052 mL, 0.648 mmol) was prepared 1-ethyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxy-1-methylethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (21 mg, 66% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.34 (d, J=7.2 Hz, 1 H), 8.55 (s, 1 H), 7.36 (s, 1 H), 7.18-7.14 (m, 2 H), 7.05-7.01 (m, 2 H), 4.28 (m, 1 H), 4.21-4.14 (m, 4 H), 3.79 (dd, J=10.8, 3.6 Hz, 1 H), 3.68 (dd, J=10.8, 6 Hz, 1 H), 1.32 (d, J=6.8 Hz, 3 H), 1.24 (t, J=6.8 Hz, 3 H); HRMS m/z calcd for C21H23FN3O4: 400.1667. Found: 400.1674.
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][CH:3]=1.[C:25]([C:27]1[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=1)#[CH:26]>>[F:12][C:11]([F:14])([F:13])[C:10]1[C:5]2[N:6]([C:2]([C:26]#[C:25][C:27]3[S:31][C:30]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:29][CH:28]=3)=[CH:3][N:4]=2)[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: C#Cc1ccc(S(N)(=O)=O)s1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3n2)cc1
Product: NS(=O)(=O)c1ccc(C#Cc2cnc3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nn23)s1

Procedure:
The title compound was prepared from 3-iodo-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazine (example C.26 step 11) (457 mg, 1 mmol) and 5-ethynyl-thiophene-2-sulfonic acid amide (example D.3) (243 mg, 1.3 mmol) according to general procedure II. Obtained as a light yellow solid (210 mg, 41%). MS (ISP) 517.1 [(M+H)+]; mp 261-263° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].[Si:7]([O:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[C:18]([O:24][CH3:25])[CH:17]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].CCCCCC.C(OCC)(=O)C>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Si:7]([O:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]([OH:21])[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:18]([O:24][CH3:25])[CH:17]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9]
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C=O
Reactant: CC(C)C[Mg]Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C(O)CC(C)C
Yield: 57 %

Procedure:
55 ml (55 mmol) of a 1.0 M solution of isobutyl magnesium bromide in tetrahydrofuran were added to a solution of 23.6 g (73.1 mmol) of tetrabutyl ammonium bromide in 50 ml of tetrahydrofuran, and the resulting mixture was immediately cooled in a dry ice-acetone bath, after which a solution of 10.25 g (36.5 mmol) of 4-t-butyldimethylsilyloxymethyl-2-methoxybenzaldehyde (prepared as described in Preparation 40) in 60 ml of tetrahydrofuran were added dropwise over 30 minutes. After the dropwise addition, the reaction temperature was gradually allowed to return to room temperature, and then the reaction was terminated by adding a saturated aqueous solution of ammonium chloride. The reaction mixture was then extracted with diethyl ether, and the extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 250 g of silica gel using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 3:1 to 2:1 by volume as the eluent, to give 6.81 g (yield 57%) of the title compound as an oily substance.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.[CH3:11][O:12][C:13]1[C:18]2[O:19][C:20]([C:22](OC)=O)=[CH:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.S(=O)(=O)(O)O>O1CCCC1.O>[CH3:11][O:12][C:13]1[C:18]2[O:19][C:20]([C:22]3[O:5][N:4]=[C:2]([CH3:3])[CH:1]=3)=[CH:21][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc2cccc(OC)c2o1
Reactant: CC(C)=NO
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2cc(-c3cc(C)no3)oc12
Temperature: 0 °C
Yield: 16.9 %

Procedure:
Thionyl chloride (10 ml) was added dropwise to methanol (100 ml) with stirring under ice-cooling. 7-Methoxybenzo(b)furan-2-carboxylic acid (10 g) was successively added, and the mixture was refluxed under heating for 1 hr. After cooling, the solvent was evaporated under reduced pressure and the precipitated yellow crystals were collected by filtration to give methyl 7-methoxybenzo(b)furan-2-carboxylate (11.2 g). This was used in the next reaction without purification. Acetone oxime (4.8 g) was dissolved in tetrahydrofuran (100 ml), and butyllithium (1.6M hexane solution) (80 ml) was added dropwise to this solution at −5° C. with stirring. Thereafter, the mixture was stirred under ice-cooling for 1 hr, and a solution (50 ml) of methyl 7-methoxybenzo(b)furan-2-carboxylate (11.2 g) in tetrahydrofuran was added. The mixture was stirred at room temperature for 20 hr. A solution of sulfuric acid (28 g) dissolved in tetrahydrofuran (120 ml)-water (30 ml) was prepared, into which the reaction mixture was poured. The mixture was refluxed under heating for 2 hr. After cooling, the reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:32]([N:33]([CH2:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])[CH3:34])=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=[C:15]([F:25])[CH:14]=1)=[O:11])=[O:5].[CH:41](OCC)(OCC)OCC>>[F:25][C:15]1[CH:14]=[C:13]([NH:12][C:10]([C:9]2[CH:8]=[C:7]([N:6]3[C:4](=[O:5])[C:3]4[C:2](=[C:32]([N:33]([CH2:35][CH2:36][CH2:37][N:38]([CH3:39])[CH3:40])[CH3:34])[CH:31]=[CH:30][CH:29]=4)[N:1]=[CH:41]3)[CH:28]=[CH:27][CH:26]=2)=[O:11])[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:16]=1
Reactant: CCOC(OCC)OCC
Reactant: CN(C)CCCN(C)c1cccc(C(=O)Nc2cccc(C(=O)Nc3cc(F)cc(N4CCOCC4)c3)c2)c1N
Product: CN(C)CCCN(C)c1cccc2c(=O)n(-c3cccc(C(=O)Nc4cc(F)cc(N5CCOCC5)c4)c3)cnc12

Procedure:
Using an analogous procedure to that described in Example 1, 3-{2-amino-3-[N-(3-dimethylaminopropyl)-N-methylamino]benzamido]-N-(3-fluoro-5-morpholinophenyl)benzamide was reacted with triethyl orthoformate. The reaction product was purified by column chromatography on an isolute SCX ion exchange column using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound Mass Spectrum: M+H+ 559.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:6][C:7]1[CH:8]=[C:9]([OH:17])[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][CH:12]=1.Cl>CO>[OH2:5].[CH3:12][C:7]1[CH:6]=[C:1]([OH:5])[C:2]([C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:3][C:4]=1[CH:11]([C:12]1[CH:11]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:9]([OH:17])=[CH:8][C:7]=1[CH3:6])[CH2:10][CH:9]([C:12]1[CH:11]=[C:10]([C:13]([CH3:14])([CH3:16])[CH3:15])[C:9]([OH:17])=[CH:8][C:7]=1[CH3:6])[CH3:8]
Reactant: C/C=C/C=O
Reactant: Cc1ccc(C(C)(C)C)c(O)c1
Agent: Cl
Solvent: CO
Product: Cc1cc(O)c(C(C)(C)C)cc1C(C)CC(c1cc(C(C)(C)C)c(O)cc1C)c1cc(C(C)(C)C)c(O)cc1C
Product: O
Yield: 160.4 %

Procedure:
Crotonaldehyde (140 g, 2 moles) is gradually added dropwise to a stirred mixture of 984 g (6 moles) of 3-methyl-6-tert-butylphenol, 700 g of methanol and 350 ml of concentrated hydrochloric acid under gentle refluxing. Refluxing is then continued for an hour. The reaction mixture is cooled, and the precipitate is collected by filtration, washed first with 2,000 ml of 80% methanol to remove byproducts and unreacted starting materials contained in the precipitate and then with water until no inorganic substances can be detected any longer, and dried at 65°-70° C. for 5 hours, to give 903 g of 1,1,3-tris(2-methyl-4-hydroxy-5-tert-butylphenyl)butane hydrate.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:10]1([CH3:17])[C:11]([CH3:16])=[CH:12][CH:13]=[CH:14][CH:15]=1.C(C(CCCC)C[NH2:22])C>O>[CH2:11]([CH:10]([CH2:15][CH2:14][CH2:13][CH3:12])[CH2:17][C:3]1[N:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([NH2:22])=[O:9])[CH3:16]
Reactant: Cc1ccccc1C
Reactant: O=C(O)c1cccnc1
Reactant: CCCCC(CC)CN
Solvent: O
Product: CCCCC(CC)Cc1ncccc1C(N)=O
Temperature: 210 °C

Procedure:
Nicotinic acid (75 g, 0.61 mmoles) and 20 g of xylene were charged to a reactor that is equipped with a sub-surface nitrogen flow, a Dean-Stark trap filled with 20 g of xylene, and a mechanical stirrer. 2-Ethylhexylamine (86.2 g, 0.67 moles) was added to this mixture dropwise. The mixture was heated to up to 210° C. and held until about 9 mL of water collected in the Dean-Stark trap. The mixture was then vacuum stripped to provide a dark residue that contained about 12.1% nitrogen and had infra-red bands at 3300, 1636.7, 1542.1, and 706 cm−1.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C@H:10]([C:22]2[C:32]3=[C:33]4[C:28](=[CH:29][CH:30]=[CH:31]3)[CH2:27][CH2:26][CH2:25][N:24]4[CH:23]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.[CH:50]1(C(Cl)=O)[CH2:53][CH2:52][CH2:51]1>C(Cl)Cl>[CH:50]1([C:6]([N:8]2[CH2:12][C@@H:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[C@H:10]([C:22]3[C:32]4=[C:33]5[C:28](=[CH:29][CH:30]=[CH:31]4)[CH2:27][CH2:26][CH2:25][N:24]5[CH:23]=3)[CH2:9]2)=[O:5])[CH2:53][CH2:52][CH2:51]1
Reactant: O=C(Cl)C1CCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CCC1)N1C[C@@H](c2c[nH]c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35852.2 %

Procedure:
To a solution of (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 450 μmol) in DCM (5 mL) under a nitrogen atmosphere was added 4M HCl in dioxane (1.7 mL, 6.8 mmol). The mixture was stirred at room temperature for 2 h. The solvent was then removed under vacuum and the residue dissolved in DCM (5 mL). DIPEA (320 μL, 1.8 mmol) and cyclobutylcarbonyl chloride (64 mg, 0.54 μmol) were added and the mixture stirred at room temperature for 16 h. The solvent was removed under vacuum and the residue dissolved in DCM, washed with saturated sodium carbonate solution and water and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/hexanes) and recrystallised from methanol to yield cyclobutyl-[(3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidin-1-yl]-methanone as a white solid 82 mg, 43%). M.p.=253-255° C.; 1H NMR (400 MHz, DMSO-d6) δ: 10.80 (dd, J=8.0 and 2.0 Hz, 1H), 7.54 (dd, J=17.6 and 8.0 Hz, 1H), 7.36 (dd, J=18.0, 8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.20-7.16 (m, 2H), 7.01 (t, J=7.6 Hz, 1H), 6.93-6.88 (m, 1H), 6.86-6.81 (m, 1H), 6.76 (m, 1H), 4.10-3.87 (m, 6H), 3.52-3.29 (m, 3H), 2.82 (t, J=6.0 Hz, 2H), 2.24-2.00 (m, 6H), 1.87 (m, 1H), 1.75 (m, 1H). LCMS: m/e 424.16 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Li]CCCC.CCCCCC.CON(C)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]>C1COCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH:7]=1)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]
Reactant: Cc1ccc(Cl)cc1Br
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To a solution of 2-bromo-4-chloro-1-methylbenzene (53 g, 0.26 mol) in anhydrous THF (600 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (103 mL, 0.26 mol). After stirring for 1 hr at −78° C., a solution of the (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (67 g, 0.246 mol) in anhydrous THF (300 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 hr. The mixture was quenched with saturated NH4Cl solution (500 mL) and extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(5-chloro-2-methylbenzoyl)piperidine-1-carboxylate (86 g), which was used immediately in the next step without purification.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.Cl[C:30]1[CH:31]=[C:32]([CH:38]=[CH:39][CH:40]=1)/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:35](=[O:36])/[CH:34]=[CH:33]/[C:32]4[CH:38]=[CH:39][C:40]([Cl:1])=[CH:30][CH:31]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: Cl
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-3-chloro-cinnamic acid, by the method of Example 1, step K, giving a solid that was a mixture of cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C30H35ClN4O2: 519 (M+H). Found: 519
Reaction SMILES: CS[C:3]1[C:8]2=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]3)[CH:10]=[CH:11][N:7]2[N:6]=[CH:5][N:4]=1.C(O)(C(F)(F)F)=O.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[C:41]([F:46])[CH:40]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>ClCCl.C1COCC1>[NH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:3]2[C:8]3=[C:9]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]4)[CH:10]=[CH:11][N:7]3[N:6]=[CH:5][N:4]=2)=[C:41]([F:46])[CH:40]=1
Reactant: CSc1ncnn2ccc(CN3CCC(O)CC3)c12
Reactant: Nc1ccc(O)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ncnn3ccc(CN4CCC(O)CC4)c23)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
To 1-((4-(methylthio)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-4-ol (188 mg, 0.675 mmol) in dichloromethane (7 mL) at 0° C. was added TFA (78 μL, 1.01 mmol) followed by m-CPBA (166 mg, 0.675 mmol, ˜70% pure). After stirring at 0° C. for 1 h, the mixture was concentrated in vacuo. Ether (20 mL) was added and then decanted off to remove the benzoic acid. The resulting crude sulfoxide was dried under high vacuum. 4-Amino-2-fluorophenol (343 mg, 2.7 mmol) was dissolved in THF (10 mL), cooled to −78° C., and charged with NaHMDS (2.7 mL, 2.7 mmol, 1 M in THF). After stirring at 0° C. for 5 min, the crude sulfoxide in THF (3 mL) was added. The reaction was stirred at 0° C. for 30 min and was then concentrated in vacuo. The residue was suspended in EtOAc (20 mL), washed with water (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by reverse phase prep HPLC and the appropriate fractions were concentrated in vacuo to remove methanol. The resulting aqueous solution was made basic with 5% aqueous sodium bicarbonate solution and extracted with EtOAc (3×10 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give 36 mg (15%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 8.04 (s, 1H), 8.00 (d, 1H, J=2.8 Hz), 7.02 (t, 1H, J=8.8 Hz), 6.88 (d, 1H, J=2.8 Hz), 6.51 (dd, 1H, J=12.8, 2.8 Hz), 6.46–6.42 (m, 1H), 5.45 (br s, 2H), 3.83 (s, 2H), 3.18 (m, 1H), 2.76–2.71 (m, 2H), 2.12–2.06 (m, 2H), 1.72–1.67 (m, 2H), 1.41–1.38 (m, 2H); MS(ESI+) m/z 358.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].Cl.[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][Cl:28])[CH3:24]>>[ClH:28].[CH2:23]([N:25]([CH2:29][CH3:30])[CH2:26][CH2:27][N:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]=2[S:8][C:7]1=[N:6][C:5]1[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:24]
Reactant: Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [H-]
Agent: [Li+]
Product: CCN(CC)CCn1c(=Nc2ccc(C)cc2)sc2ncccc2c1=O
Yield: 41.1 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.34 mmol) of 2-(4-methylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 54 mg of lithium hydride and 633 mg of 2-diethylaminoethylchloride hydrochloride were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform-3% methanol). The resulting compound was then recrystallized from a mixture of ether and hexane containing 4 N hydrogen hydride in dioxane to obtain 556 mg of 3-(2-diethylaminoethyl)-2,3-dihydro-2-[(4-methylphenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one monohydrochloride.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][N:14]3[CH3:19])[C:9](=[O:11])[NH:10][C:5]2=[N:4][CH:3]=1.BrC1N=C(N[CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31]N2C)C(N)=NC=1.C(N1C=CN=C1)(N1C=CN=C1)=[O:38]>O1CCCC1>[OH:38][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[N:7]=[C:6]3[N:8]([CH2:12][CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][N:14]4[CH3:19])[C:9](=[O:11])[NH:10][C:5]3=[N:4][CH:3]=2)=[CH:31][CH:28]=1
Reactant: CN1CCCCC1Cn1c(=O)[nH]c2ncc(Br)nc21
Reactant: CN1CCCCC1CNc1nc(Br)cnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1CCCCC1Cn1c(=O)[nH]c2ncc(-c3ccc(O)cc3)nc21
Yield: 92 %

Procedure:
6-Bromo-1-((1-methylpiperidin-2-yl)methyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. A solution of 6-bromo-N2-((1-methylpiperidin-2-yl)methyl)pyrazine-2,3-diamine (0.48 g, 1.599 mmol) and 1,1′-carbonyldiimidazole (0.324 g, 1.999 mmol) in anhydrous tetrahydrofuran (15 mL) was heated overnight at 115° C. The volatiles were removed under reduced pressure, and the crude product was purified by Biotage column chromatography (0-15% methanol in dichloromethane) to provide the title compound (0.48 g, 1.472 mmol, 92% yield). MS (ESI) m/z 327.2 [M+1]+.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:25].[Na+]>CO>[C:1]([NH:5][S:6]([CH2:9][CH:10]([NH2:25])[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)CC(=O)c1ccc(F)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)CC(N)c1ccc(F)cc1

Procedure:
A solution of 0.66 g of N-(tert-butyl)-2-(4-fluorophenyl)-2-oxoethanesulfonamide, 1.85 g of ammonium acetate and 0.17 g of sodium cyanoborohydride in 12 ml of methanol was stirred at 60° C. for 17 hours. After the removal of the solvent under reduced pressure, the residue was taken up in 50 ml of ethyl acetate and washed twice with 30 ml of 0.5 N aqueous sodium hydroxide solution and 30 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude product was subjected to a chiral separation.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]3[C:16]([CH3:21])=[N:17][O:18][C:19]=3[CH3:20])[CH:13]=2)[NH:8][C:7]1=[O:22])C.O[Li].O.Cl>C1COCC1.CO.O>[CH3:21][C:16]1[C:15]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:22])[C:6]3([CH2:5][C:4]([OH:29])=[O:3])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:19]([CH3:20])[O:18][N:17]=1
Reactant: CCOC(=O)CC1(c2ccccc2)C(=O)Nc2ccc(-c3c(C)noc3C)cc21
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(CC(=O)O)(c1ccccc1)C(=O)N2
Temperature: 25 °C
Yield: 62 %

Procedure:
Ethyl-2-(5-(3,5-dimethyl isoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)acetate (35 mg, 0.089 mmol) dissolved in THF/MeOH (2 mL/2 mL) was added LiOH.H2O (40 mg) in H2O (2 mL). The reaction was stirred at room temperature until complete consumption of the starting material as indicated by TLC. The reaction was added water, acidified with 3% HCl until pH<1 and extracted with EtOAc (3×5 mL). The combined extracts were washed with brine, dried over MgSO4 and concentrated under vacuum. The title compound was purified on Pre-TLC to afford the title compound as a white solid (20 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δH 12.17 (s, 1H), 10.56 (s, 1H), 7.41 (s, 1H), 7.35-7.29 (m, 4H), 7.22-7.24 (m, 2H), 6.96 (d, J=8.0 Hz, 1H), 3.29-3.30 (m, 2H), 2.38 (s, 3H), 2.21 (s, 3H). MS (ESI) m/e [M+1]+ 363.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][N:15]3[CH3:18])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:19](Cl)(=O)[C:20](Cl)=[O:21].Cl.C([O:29][C:30](=[NH:45])[CH2:31][C:32]1[C:40]2[C:35](=[CH:36][C:37]([N+:41]([O-:43])=[O:42])=[CH:38][CH:39]=2)[N:34]([CH3:44])[CH:33]=1)(C)C.C(N(CC)CC)C>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:19]4[C:20](=[O:21])[NH:29][C:30](=[O:45])[C:31]=4[C:32]4[C:40]5[C:35](=[CH:36][C:37]([N+:41]([O-:43])=[O:42])=[CH:38][CH:39]=5)[N:34]([CH3:44])[CH:33]=4)=[CH:14][N:15]3[CH3:18])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)OC(=N)Cc1cn(C)c2cc([N+](=O)[O-])ccc12
Reactant: Cn1ccc2ccc(OCCn3ccnc3)cc21
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccc(OCCn3ccnc3)cc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 26.2 %

Procedure:
6-(2-Imidazol-1-yl-ethoxy)-1-methyl-1H-indole (185 mg, 0.77 mmol) was dissolved in CH2Cl2 (2 mL) under argon at 0° C. To this was added oxalyl chloride (0.19 mL, 2.18 mmol) in CH2Cl2 (2 mL). After stirring at 0° C. for 4 h, the mixture was evaporated and dried under vacuum for 2 h. 2-(1-Methyl-6-nitro-1H-indol-3-yl)acetimidic acid isopropyl ester hydrochloride (239 mg, 0.77 mmol) and CH2Cl2 (3mL) were added to the above green solid. Triethylamine (0.81 mL, 5.82 mmol) was added slowly at 0° C. and the mixture was stirred at room temperature for 16 h. The mixture was evaporated to dryness and methanol (5 mL) and 12 N hydrochloric acid (1 mL) were added. The mixture was heated to 85° C. for 1 h. After the solvents were evaporated, ethyl acetate (50 mL) was added and the mixture was carefully washed with 5% sodium bicarbonate (3×50 mL). The aqueous layer was back-extracted with ethyl acetate (2×50 mL), then the combined organic extracts were dried (MgSO4), filtered though a pad of silica gel and the pad was washed with 10% methanol/CH2C2 (400 mL). The filtrates were concentrated and the crude product was chromatographed on silica gel with 1% to 5% methanol/ethyl acetate gave an orange solid. Further purification by dissolving the solid in hot CH2C2 (3 mL) and precipitating with ether (20 mL) yielded 3-[6-(2-imidazol-1-yl-ethoxy)-1-methyl-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione as an orange solid (0.103 g, 26%).