Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C@@H:27]2[CH2:33][C:32]([F:35])([F:34])[CH2:31][CH2:30][N:29](CC3C=CC(OC)=CC=3OC)[C:28]2=[O:47])(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C@@H:27]2[CH2:33][C:32]([F:34])([F:35])[CH2:31][CH2:30][NH:29][C:28]2=[O:47])(=[O:24])=[O:25])=[CH:19][CH:18]=1
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](NS(=O)(=O)c3ccc(Cl)cc3)C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
A cocktail containing 40% trifluoroacetic acid, 1% trifluoromethanesulfonic acid in CH2Cl2 (20 ml) was added to 4-chloro-N-[(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-benzenesulfonamide (0.5 g, 1.0 mmol). After 30 min the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with water, NaHCO3 solution, 1 M KHSO4 solution, brine, dried (MgSO4.2H2O), filtered, concentrated under reduce pressure and purified over silica gel (CH2Cl2/MeOH 95:5 v/v): white solid 0.74 g (78%);
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:23]2[CH2:24][CH2:25][CH:20]([NH2:19])[CH2:21][CH2:22]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC(N)CC2)nc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6-chloronicotinic acid ethyl ester (4.27 g, 23 mmol) was dissolved in DMF (30 ml), and potassium carbonate (4.77 g, 35 mmol) and 4-aminopiperidine (2.76 g, 28 mmol) were added thereto, followed by stirring at 80° C. for 3 hours and at 100° C. for 1 hour. After the reaction mixture was cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure, thereby obtaining 6-(4-aminopiperidin-1-yl)nicotinic acid ethyl ester (4.17 g, 73%) as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[S:11](N)(N)(=[O:13])=[O:12].N1C=CC=CC=1.O>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:9])[S:11](=[O:13])(=[O:12])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CNc1nc(Cl)ccc1N
Reactant: NS(N)(=O)=O
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN1c2nc(Cl)ccc2NS1(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottom flask was added 6-chloro-N2-methylpyridine-2,3-diamine (1-2) (2.043 g, 12.96 mmol), sulfamide (2.69 g, 28.0 mmol), and anhydrous pyridine (20 ml). The reaction mixture was refluxed at 125 C in a hot oil bath with stirring under an atmosphere of nitrogen with a water cooled reflux condenser attached overnight (16 hours). The reaction mixture was then cooled to room temperature and suspended in EtOAc (250 mL) & 6N HCl in water (250 mL) and filtered. Filtrate was then separated, organics dried over sodium sulfate, filtered & concentrated. The resulting residue was then purified with silica gel chromatography (0-20% Isopropanol/DCM) & concentrated to yield 5-chloro-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (23-1). HRMS (M+H)+: observed=219.9946, calculated=219.9942.
Reaction SMILES: [N:1]1([C:7]([C:9]2[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18](O)=[O:19])=[CH:13][CH:12]=3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:26]12[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:30][NH:29][CH2:28][CH2:27]2>>[CH2:30]1[N:29]([C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH2:21][C:22]([F:25])([F:23])[F:24])[C:9]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])=[CH:17]3)=[O:19])[CH2:28][CH2:27][N:26]2[CH2:34][CH2:33][CH2:32][CH:31]12
Reactant: C1CC2CNCCN2C1
Reactant: O=C(O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F)N1CCN2CCCC2C1
Yield: 65 %

Procedure:
The title compound was synthesized in analogy to example 46, intermediate e), from 2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylic acid and 1,4-diazabicyclo[4.3.0]nonane (purchased at Matrix Ref 8078), to give the desired product as a white solid (65%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.[C:22]1([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][S:16][C:14]3[S:15][C:11]4[CH2:10][CH2:9][C:8]5[C:17](=[CH:18][CH:19]=[CH:20][C:7]=5[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=4[N:13]=3)=[CH:34][CH:35]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1CCc1sc(SCc3ccc(-c4ccccc4)cc3)nc1-2
Yield: 68 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy)acetate and 4-phenylbenzyl bromide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 68%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1I.CC(CCC)C(=O)C(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.Cl[Cu].CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:15]2[C:10]([F:9])=[CH:11][CH:12]=[CH:13][C:14]=2[F:16])=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)c(F)c1
Reactant: Sc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: CCCC(C)C(=O)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Fc1cccc(F)c1Sc1ccc(Br)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
N-Methyl-2-pyrrolidone (10 mL) was added to 4-bromothiophenol (0.500 g, 2.64 mmol) in a sealed tube and the mixture was purged with argon for 5 minutes. After this time, 2,4-difluoroiodobenzene (0.63 g, 2.64 mmol), CuCl (0.131 g, 1.32 mmol), tetramethyl heptanedione (0.14 mL, 0.66 mmol) and cesium carbonate (1.70 g, 5.28 mmol) were added to the reaction mixture. The reaction mixture was stirred at 130° C. under argon for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. Silica gel chromatography (neat hexanes) provided impure 1-(4-bromo-phenylsulfanyl)-2,6-difluorobenzene (0.29 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]2/[C:9](=[CH:15]\[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)/[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:5]=2[CH:4]=1>C1(C)C=CC=CC=1.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]2[CH:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cn1)/C(=C\c1ccccn1)C(=O)CCC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc2c(cn1)C(Cc1ccccn1)C(=O)CCC2
Yield: 73 %

Procedure:
(E)-3-Methoxy-9-(pyridin-2-ylmethylene)-6,7-dihydro-5H-cyclohepta[c]pyridin-8 (9H)-one (127, R5=Pyridin-2-yl) (36.15 g, 129 mmol) in toluene (800 mL) with 20 wt % (wet) palladium hydroxide on carbon (4.53 g, 6.45 mmol) was stirred under a hydrogen filled balloon for about 7 h. The catalyst was removed by filtration through a pad of Celite® then the pad was washed with toluene (250 mL). The filtrate was concentrated under reduced pressure then the material was purified on silica gel (330 g) using 100% EtOAc. Product fractions were combined and concentrated under reduced pressure to yield 3-methoxy-9-(pyridin-2-ylmethyl)-6,7-dihydro-5H-cyclohepta[c]pyridin-8(9H)-one (128, R2=Pyridin-2-ylmethyl) (26.64 g, 73%); LC/MS, method 3, Rt=1.14 min, MS m/z 283 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.48-8.43 (m, 1H), 7.79 (s, 1H), 7.71-7.64 (m, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.20-7.17 (m, 1H), 6.68 (s, 1H), 4.69-4.60 (m, 1H), 3.78 (s, 3H), 3.74-3.68 (m, 1H), 3.25-3.06 (m, 2H), 2.92-2.78 (m, 2H), 2.49-2.43 (m, 1H), 2.15-2.01 (m, 1H), 1.75-1.57 (m, 1H).
Reaction SMILES: [NH:1]1[CH:6]=[C:5]([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:9][N:10]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=23)[CH:4]=[CH:3][C:2]1=[O:22].[H-].[Na+].I[CH3:26].[Na+].[Cl-]>CN(C=O)C>[CH3:26][N:1]1[CH:6]=[C:5]([C:7]2[C:8]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:9][N:10]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=23)[CH:4]=[CH:3][C:2]1=[O:22]
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccncc23)c[nH]1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2c(-c3ccccc3)nn3ccncc23)ccc1=O
Reaction time: 0.17 h

Procedure:
To a suspension of 3-(2(1H)-pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine (120 mg) in DMF (3 mL) was added NaH (60% oil suspension, 25 mg) at room temperature and the mixture was stirred at the same temperature for 10 min. To the mixture was added iodomethane (0.039 mL). After stirring at room temperature for 15 h, the reaction mixture was poured into 10% NaCl solution, extracted with EtOAc, washed with 10% NaCl solution and brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (EtOAc to CH2Cl2-MeOH 10:1) to give 3-(1-methyl-2(1H)-pyridinon-5-yl)-2-phenylpyrazolo[1,5-a]pyrazine (114.5 mg) as a solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH2:26][OH:27])=[CH:20]2>>[C:1]([C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH2:26][OH:27])=[CH:20]3)=[O:15])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)O)cn1
Reactant: Nc1ccc2[nH]c(CO)cc2c1
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccc3[nH]c(CO)cc3c2)cn1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)(3-pyridyl)]prop-2-enoic acid, Example 44(b), (41 mg, 0.20 mmol) and (5-aminoindol-2-yl)methan-1-ol, Example 74(b), (32 mg, 0.20 mmol) provided, after purification by silica gel chromatography (20:80 hexane:EtOAc), the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 350 (M+1).
Reaction SMILES: Br.[NH2:2][C:3]1[N:8]([CH3:9])[C:7](=[O:10])[C:6]([C:11]2[CH:12]=[N:13][C:14]([O:17]C)=[CH:15][CH:16]=2)=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[N:4]=1>C(O)(=O)C>[NH2:2][C:3]1[N:8]([CH3:9])[C:7](=[O:10])[C:6]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[N:4]=1
Reactant: COc1ccc(-c2c(-c3cccc(F)c3)nc(N)n(C)c2=O)cn1
Agent: Br
Solvent: CC(=O)O
Product: Cn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O

Procedure:
In a mixture solution of acetic acid and 48% hydrogen bromide, 2-amino-6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-3-methyl-3,4-dihydro-4-pyrimidinone was stirred at 100° C. for 2 hours. After cooling, the reaction solution was basified and washed with ethyl acetate. The aqueous layer was neutralized with diluted hydrochloric acid, and the resulting solid was collected by filtration, to give the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([N:9]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[OH:20])[CH2:12][C:11]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:10]2)=[O:8])=[CH:4][CH:3]=1.O.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][NH:39][CH:40]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:38]1[CH:37]=[C:36]([C:2]2[S:6][C:5]([C:7]([N:9]3[CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[OH:20])[CH2:12][C:11]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[N:10]3)=[O:8])=[CH:4][CH:3]=2)[CH:40]=[N:39]1
Reactant: O=C(c1ccc(Br)s1)N1N=C(c2cccnc2)CC1c1ccccc1O
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2cn[nH]c2)s1)N1N=C(c2cccnc2)CC1c1ccccc1O
Reaction time: 0.25 h
Yield: 23.8 %

Procedure:
To a solution of 2-{1-[(5-bromo-2-thienyl)carbonyl]-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl}phenol (0.209 g, 0.488 mmol) in MeOH (1 mL), DMF (1 mL), and water (1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.110 g, 0.567 mmol), tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol) and cesium carbonate (0.318 g, 0.976 mmol). The reaction mixture was subjected to MWI at 100° C. for 15 minutes. A precipitate formed and was filtered and washed with water to give 0.197 grams of crude product as a tan solid. The crude material was purified by column chromatography to give 2-(1-{[5-(1H-pyrazol-4-yl)-2-thienyl]carbonyl}-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (I-45) (0.048 g, 0.116 mmol) as a white solid. LCMS: (FA) ES+ 416.3, ES 414.3. 1H NMR (400 MHz, d6-DMSO) δ: 9.73-9.82 (bs, 1H), 9.11 (s, 1H), 8.78 (d, 1H), 8.54 (d, 1H), 8.12 (s, 2H), 7.96 (d, 1H), 7.74-7.80 (m, 1H), 7.29 (d, 1H), 7.08 (t, 1H), 6.92 (d, 1H), 6.85 (d, 1H), 6.72 (t, 1H), 5.85 (dd, 1H), 3.90 (dd, 1H), and 3.21 (dd, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@H:10]([O:14][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCC/C=C\CCCCCOS(C)(=O)=O
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Product: CCCCCCCCCCC/C=C\CCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCC/C=C\CCCCCCCCCCC

Procedure:
Compound VI-7 (196 mg, 40.7%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 134 mg, 0.693 mmol) and (Z)-octadec-6-enyl methanesulfonate (Nu-Chek Prep, Inc; 600 mg, 1.73 mmol).
Reaction SMILES: [O:1]=[C:2]1[CH:9]2[CH2:10][C:5]3([C:12](O)=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][NH2:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:24][O:23][C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[CH:22]=1)[CH2:25][NH:26][C:12]([C:5]12[CH2:4][CH:3]3[CH2:11][CH:7]([CH2:8][CH:9]([C:2]3=[O:1])[CH2:10]1)[CH2:6]2)=[O:13]
Reactant: O=C1C2CC3CC1CC(C(=O)O)(C3)C2
Reactant: COc1cc(CN)cc(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNC(=O)C23CC4CC(C2)C(=O)C(C4)C3)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
4-oxoadamantane-1-carboxylic acid (200 mg, 1.03 mol), (3,5-dimethoxyphenyl)methanamine (172 mg, 1.03 mmol), EDCI (410 mg, 2.06 mmol), and HOBt (280 mg, 2.06 mmol) were dissolved in dry CH2Cl2. DIEA (1.3 g, 10 mmol) was added under nitrogen at 0° C. and the mixture was stirred overnight at rt. The mixture was washed with water and brine. The organic layer was dried and concentrated to give crude product which was purified by preparative TLC to give N-(3,5-dimethoxybenzyl)-4-oxoadamantane-1-carboxamide (231 mg, 65%). 1H NMR: (400 MHz, CDCl3): δ=1.62 (s, 4H) 1.95-2.25 (m, 13H), 2.59 (s, 2H), 3.78 (s, 3H), 3.83 (s, 3H), 4.35 (d, 2H), 6.05 (s, 1H), 6.44 (m, 2H), 7.15 (d, 1H).
Reaction SMILES: [CH2:1]([C:5]1[S:22][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-:23].[Na+]>C(O)C>[CH2:1]([C:5]1[S:22][C:8]([NH:9][C:10]2[N:11]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=2)=[C:7]([C:12]([OH:23])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCc1cc2c(=O)n3cc(C(=O)OC)ccc3nc2s1
Agent: [Na+]
Solvent: CCO
Product: CCCCc1cc(C(=O)O)c(Nc2ccc(C(=O)O)cn2)s1

Procedure:
A mixture of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid, methyl ester (Example 8), 0.94 g (0.00297 mol), 35 ml of 1 N sodium hydroxide and 25 ml of ethanol is refluxed for fifty-five minutes. The resulting solution is evaporated to dryness, and the residue is dissolved in hot water, filtered, cooled and acidified with glacial acetic acid. The precipitate is separated, washed with water and dried to give 0.7 g of 6-[(5-butyl-3-carboxy-2-thienyl)amino]-3-pyridinecarboxylic acid; mp 217° C. (dec) after recrystallization from glacial acetic acid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=O.[N:14]1([C:20](=[S:22])[NH2:21])[CH2:19]CCC[CH2:15]1>C1COCC1>[CH3:15][N:14]([CH3:19])[C:20]1[S:22][CH:2]=[C:3]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)[N:21]=1
Reactant: NC(=S)N1CCCCC1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: C1CCOC1
Product: CN(C)c1nc(-c2ccc(C(=O)O)cc2)cs1
Yield: 32.5 %

Procedure:
To a stirred mixture of thiocarbonyldiimidazole (44.9 mmol) in THF (40 mL) at room temperature was added portionwise 2 M Dimethylamine in THF (44 mmol) and a temperature increase was observed. 40 min after final addition the reaction mixture was heated to 55° C. for 1 h, then allowed to reach room temperature again. The reaction was then concentrated in vacuo and the residue purified by flash chromatography (silica gel, Petroleum ether-EtOAc) to give the intermediate imidazole-1-carbothioic acid dimethylamide. This material was treated with freshly prepared sat. ammonia in methanol (40 ml) for 60 h, then concentrated in vacuo and the precipitated residue was suspended in diethyl ether and collected by filtration. The precipitate was washed with diethyl ether and air-dried to give a slight yellow solid (1.71 g, 16.4 mmol) which was used in the subsequent step. 4-(2-bromoacetyl)benzoic acid (1.23 mmol) and 1-piperidinethiocarboxamide (1.23 mmol) were mixed in THF (10 mL), then refluxed for 3 h. The reaction mixture was then allowed to reach room temperature and the obtained precipitate was collected by filtration and washed with 3 portions of diethyl ether. The crude product was crystallized from hot 1:1 EtOH-EtOAc to give a first harvest of colorless needles (0.1 g, 0.40 mmol). 1H NMR (DMSO-d6, 400 MHz) δ 7.94 (4H, m), 7.37 (1H, s), 3.11 (6H, m).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]6[CH2:45][CH2:46][CH2:47][CH2:48][C:43]6=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]6[CH2:45][CH2:46][CH2:47][CH2:48][C:43]6=[N:42][CH:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cnc5n4CCCC5)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cnc5n4CCCC5)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methyl]thio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (460 mg) in dichloromethane (10 ml) was added a solution of 3-chloroperbenzoic acid (70%, 0.25 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, and dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 9:1→ethyl acetate), and was recrystallized from ethyl acetate-diisopropyl ether, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 405) (311.3 mg) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]=[CH:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14].B(OB=O)=O.[OH:22][C:23]1[CH:24]=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=1)[CH:28]=O.B(OCCCC)(OCCCC)OCCCC.C(N)CCC.Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11](=[O:16])[CH2:12][C:13](=[O:15])/[CH:14]=[CH:28]/[C:27]1[CH:30]=[C:23]([OH:22])[CH:24]=[CH:25][C:26]=1[O:31][CH3:32]
Reactant: CC(=O)CC(=O)C=Cc1cc(O)ccc1Br
Reactant: COc1ccc(O)cc1C=O
Agent: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: O=BOB=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCN
Product: COc1ccc(O)cc1/C=C/C(=O)CC(=O)/C=C/c1cc(O)ccc1Br
Reaction time: 1 h
Yield: 9.9 %

Procedure:
6-(2-Bromo-5-hydroxyphenyl)hex-5-ene-2,4-dione (15 mg, 53 μmol) and boron trioxide (11 mg, 0.16 mmol) was placed in a 20 mL reaction vessel, and dissolved in 0.4 mL of ethyl acetate. To the stirring mixture at 80° C. was added a solution of 5-hydroxy-2-methoxybenzaldehyde (10 mg, 0.07 mmol) and tri-n-butyl borate (25 mL, 93 μmol), sequentially. After the reaction mixture was stirred for 2 h at the same temperature, n-butylamine (10 μL, 0.10 mmol) was added with additional stirring for 1 h. The reaction mixture was treated with a 1:1 solution (1 mL) of 1N HCl and brine at room temperature, and was stirred at 50° C. for 5 min to 1 h (if necessary, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution). The organic layer was purified directly by silica gel column chromatography (eluting with hexane/ethyl acetate or chloroform/methanol) to obtain the title compound (2.2 mg, 10%) as a solid.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].Br[CH2:6][C:7]([NH:9][C:10]1[C:27]([OH:28])=[C:26]2[C:13]([CH2:14][CH:15]3[C:24]([C:25]2=[O:29])=[C:23]([OH:30])[C:22]2([OH:31])[CH:17]([CH:18]([N:37]([CH3:39])[CH3:38])[C:19]([OH:36])=[C:20]([C:33]([NH2:35])=[O:34])[C:21]2=[O:32])[CH2:16]3)=[C:12]([N:40]([CH3:42])[CH3:41])[CH:11]=1)=[O:8]>CN1C(=O)N(C)CCC1.C(#N)C>[CH3:39][N:37]([CH3:38])[C@H:18]1[C@H:17]2[C@:22]([OH:31])([C:23]([OH:30])=[C:24]3[C@H:15]([CH2:16]2)[CH2:14][C:13]2[C:26](=[C:27]([OH:28])[C:10]([NH:9][C:7](=[O:8])[CH2:6][NH:4][O:3][CH3:2])=[CH:11][C:12]=2[N:40]([CH3:41])[CH3:42])[C:25]3=[O:29])[C:21](=[O:32])[C:20]([C:33]([NH2:35])=[O:34])=[C:19]1[OH:36]
Reactant: CON
Reactant: CN(C)c1cc(NC(=O)CBr)c(O)c2c1CC1CC3C(N(C)C)C(O)=C(C(N)=O)C(=O)C3(O)C(O)=C1C2=O
Agent: Cl
Solvent: CN1CCCN(C)C1=O
Solvent: CC#N
Product: CONCC(=O)Nc1cc(N(C)C)c2c(c1O)C(=O)C1=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C[C@@H]1C2
Yield: 21.2 %

Procedure:
The compound of the example is prepared by the procedure of example 1 using 1.5 g of methoxyamine hydrochloride (neutralized by NaOH, extracted with methylene chloride), and 0.5 g of 9-(2-bromo-acetylamino)-4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carboxylic acid amide in 8 ml DMPU and 2.5 ml acetonitrile to give 0.1 g of the product.