Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]O.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].CN(C=[O:28])C>CCOCC>[Br:1][C:2]1[C:9]([O:28][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21])=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Cl)ccc1Br
Reactant: CN(C)C=O
Agent: c1c[nH]cn1
Solvent: CCOCC
Product: Cc1cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of 2-bromo-5-chlorobenzylalcohol (10 g) from Example 73 and imidazole (3.23 g) in dry DMF (50ml) was added dropwise t-butyl chloro dimethylsilane in dry DMF (10 ml) for 20 minutes at -0° C. After addition, the mixture was stirred for 30 minutes at room temperature. The mixture was diluted with ether, and washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[C:6]([OH:8])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1)#[N:2].[CH2:15]=[O:16].C(#N)C.Cl[CH:21]([F:23])[F:22]>[OH-].[K+]>[C:1]([C:3]1[C:7]([CH2:15][OH:16])=[C:6]([O:8][CH:21]([F:23])[F:22])[N:5]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:4]=1)#[N:2]
Reactant: C=O
Reactant: FC(F)Cl
Reactant: N#Cc1cc(O)n(-c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: N#Cc1nn(-c2ccccc2)c(OC(F)F)c1CO
Temperature: 25 °C
Yield: 65.5 %

Procedure:
18.5 g (0.10 mole) of the 3-cyano-5-hydroxy-1-phenylpyrazole synthesized in Reference Example 4 was dissolved in 35.0 g (0.15 mole) of a 24% aqueous potassium hydroxide solution. To the solution being stirred at room temperature was dropwise added 9.7 g (0.12 mole) of a 37% formalin solution, followed by stirring at the same temperature for 1 hour. Then, there were added 70.0 g (0.3 mole) of a 24% aqueous potassium hydroxide solution and 100 ml of acetonitrile. Therein was blown 17.3 g (0.20 mole) of chlorodifluoromethane at room temperature in 2 hours, followed by stirring at room temperature for 2 hours to give rise to a reaction. After the reaction, the organic layer which appeared by phase separation, was concentrated under reduced pressure to obtain 24.6 g (purity: 70.6%, yield: 65.5%) of a crude solution of title compound. The crude solution was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain a title compound as white crystals.
Reaction SMILES: COC1C=C(N2CCC(C3C=CC=CC=3N)C2)C=CC=1.Cl.[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=O)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.N1(CCOC2C=C[C:54]([CH2:55][NH:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[CH:63]3[CH2:67][CH2:66][N:65]([C:68]4[CH:73]=[CH:72][CH:71]=[C:70]([O:74][CH3:75])[CH:69]=4)[CH2:64]3)=CC=2)CCCCCC1>>[N:22]1([CH2:29][CH2:30][O:31][C:32]2[CH:40]=[CH:39][C:35]([CH2:36][CH2:54][CH2:55][NH:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[CH:63]3[CH2:67][CH2:66][N:65]([C:68]4[CH:73]=[CH:72][CH:71]=[C:70]([O:74][CH3:75])[CH:69]=4)[CH2:64]3)=[CH:34][CH:33]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1cccc(N2CCC(c3ccccc3NCc3ccc(OCCN4CCCCCC4)cc3)C2)c1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: COc1cccc(N2CCC(c3ccccc3N)C2)c1
Agent: Cl
Product: COc1cccc(N2CCC(c3ccccc3NCCCc3ccc(OCCN4CCCCCC4)cc3)C2)c1

Procedure:
Synthesized from 2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous method to Example 152, synthetic [4-(2-azepan-1-ylethoxy)benzyl]{2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenyl}amine (180 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl {2-[1-(3-methoxyphenyl)pyrrolidin-3-yl]phenyl}amine (153 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (140 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:11]1[NH:12][C:13]([CH:17]=[O:18])=[C:14]([I:16])[N:15]=1)[CH2:8][CH2:9][CH3:10].Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:7]([CH:11]1[N:15]=[C:14]([I:16])[C:13]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:31]([O:33][CH3:34])=[O:32])=[CH:23][CH:22]=2)([CH:17]=[O:18])[NH:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1nc(I)c(C=O)[nH]1
Reactant: COC(=O)c1ccc(CBr)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1N=C(I)C(C=O)(Cc2ccc(C(=O)OC)c3ccccc23)N1
Temperature: 70 °C
Reaction time: 15 h
Yield: 84.8 %

Procedure:
A suspension of 29.53 g (0.214 mol) of powdered potassium carbonate, 60.00 g (0.214 mol) of 2-butyl-4-iodoimidazole-5-carboxaldehyde, and 65.68 g (0.235 mol) of methyl 4-bromomethylnaphthalene-1-carboxylate (E. A. Dixon, A. Fischer, and F. P. Robinson, Can. J. Chem. 59, 2629 (1981)) in 600 ml of dimethylformamide was stirred for 5 hours under argon at 70° C. An additional 6.56 g (0.0235 mol) of the bromomethyl ester was added and the suspension was stirred an additional 15 hours at 70° C. The mixture was poured into water and the solid which separated was collected by filtration, washed with water, and triturated several times with 250 ml of boiling methanol to give 86.8 g (85%) of a solid; mp 177.5°-179° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:18])[CH:14]=2)[CH:9]1[C:19](O)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:24]=1[NH2:25].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:18])[CH:14]=2)[CH:9]1[C:19](=[O:20])[NH:25][C:24]1[C:23]([F:22])=[CH:29][CH:28]=[CH:27][C:26]=1[F:30])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(F)ccc2C1C(=O)O
Reactant: Nc1c(F)cccc1F
Solvent: c1ccncc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCc2cc(F)ccc2C1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
To a solution of 6-fluoro-3,4-dihydro-1H-isoquinoline-1,2-dicarboxylic acid 2-tert-butyl ester (0.37 g, 1.25 mmol, Eq: 1.00) and 2,6-difluoroaniline (194 mg, 162 μl, 1.5 mmol, Eq: 1.2) in Pyridine (7 mL) at 0° C. was added phosphorus oxychloride (288 mg, 175 μl, 1.88 mmol, Eq: 1.5). The reaction was warmed to RT, stirred for 18 h, diluted with water and extracted with EtOAc. The combined organics were washed with 1 N HCl, water, brine, dried with Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.2181 g 1-(2,6-difluoro-phenylcarbamoyl)-6-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester as white foam. 42.8% MS m/z 428.9 (M+H)
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:13])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(=O)([O-])O.[Na+]>O1CCCC1>[OH:12][C:11]1[C:3]([NH:2][C:21](=[O:23])[CH3:22])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1O)C(=O)CC2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1O)C(=O)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
6-Amino-7-hydroxyindan-1-one hydrobromide (800 mg, 3.28 mmol) was suspended in tetrahydrofuran (20 mL), triethylamine (571 μL, 4.10 mmol) and acetic anhydride (387 μL, 4.10 mmol) were added, and the mixture was stirred at room temperature for 1.5 hr. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=60/40→100/0) to give the title compound (481 mg, yield 71%).
Reaction SMILES: [OH:1][C@H:2]([CH2:34][OH:35])[CH2:3][C@H:4]([NH:15][C:16]([C:18]1[C:19]2[CH:26]=[N:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:20]=2[CH:21]=[N:22][CH:23]=1)=[O:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=1.C1N=CN([C:41](N2C=NC=C2)=[O:42])C=1.O>CN(C=O)C>[CH3:14][S:11]([C:7]1[CH:6]=[C:5]([C@@H:4]([NH:15][C:16]([C:18]2[C:19]3[CH:26]=[N:25][N:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[C:20]=3[CH:21]=[N:22][CH:23]=2)=[O:17])[CH2:3][CH:2]2[CH2:34][O:35][C:41](=[O:42])[O:1]2)[CH:10]=[CH:9][N:8]=1)(=[O:12])=[O:13]
Reactant: CS(=O)(=O)c1cc([C@H](C[C@H](O)CO)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc([C@H](CC2COC(=O)O2)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a chilled (0° C.) solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(1S,3S)-3,4-dihydroxy-1-(2-methanesulfonyl-pyridin-4-yl)-butyl]-amide (50.0 mg, 0.100 mmol) in DMF (1 mL) was added CDI (32.4 mg, 0.200 mmol). The mixture was then allowed to warm to room temperature. After 12 hours, the reaction was poured in to water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with aqueous ammonium chloride (3×10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-6% methanol in methylene chloride. The solid from the column chromatography was crystallized from methylene chloride to afford the title compound as white needle-shaped crystals. MS m/z 526.64 (MH+).
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.[Cl:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](N(OC)C)=[O:22])=[CH:19][CH:18]=1>C1COCC1>[Cl:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](=[O:22])[C:7]#[C:6][C:4]([CH3:8])([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])[CH3:5])=[CH:19][CH:18]=1
Reactant: C#CC(C)(C)O[Si](C)(C)C
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccc(Cl)cc1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (11.79 g, 75.15 mmol) in dry THF (100 mL), n-BuLi (14.08 mL, 22.54 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. After being stirred for 30 min at −78° C., a solution of 4-chloro-N-methoxy-N-methylbenzamide (5.0 g, 25.0 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 1 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5-7% EtOAc in hexanes to afford 1-(4-chlorophenyl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (3.8 g, 57%) as a light green oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:24][C:25]1[CH:26]=[C:27]([NH:34][C:35]([CH2:37][O:38]C(=O)C)=[O:36])[CH:28]=[CH:29][C:30]=1[NH:31][CH2:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:24][C:25]1[CH:26]=[C:27]([NH:34][C:35](=[O:36])[CH2:37][OH:38])[CH:28]=[CH:29][C:30]=1[NH:31][CH2:32][CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1ccc(NC(=O)COC(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CCNc1ccc(NC(=O)CO)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Yield: 21.2 %

Procedure:
To a 50 mL flask was added the product of Example 157 (0.19 g, 0.32 mmol), CHCl3 (5 mL), MeOH (10 mL), water (2 mL), and potassium carbonate (0.22 g, 1.6 mmol). After 4 h the reaction mixture was diluted with CHCl3 (40 mL), and the organic phase was partitioned, washed with water (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude sample was chromatographed (silica gel, 0-10% MeOH/DCM) to afford the title compound (37 mg, 21%). 1H-NMR (CDCl3): δ 8.14 (1H, s), 7.42-7.48 (3H, m), 7.27-7.33 (5H, m), 7.15 (1H, t), 7.09 (1H, dd), 6.99 (1H, d), 6.56 (1H, d), 5.15 (2H, s), 4.14 (2H, s), 3.71 (3H, s), 2.95 (2H, q), 0.99 (3H, t); MS(ESI): 546 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)[NH2:20]>>[ClH:1].[CH3:25][O:24][C:22]1[CH:21]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[CH:23]=1)[NH:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1cc(N)cc(OC)c1
Product: COc1cc(Nc2cc(C)nc(-c3ccccn3)n2)cc(OC)c1
Product: Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3,5-dimethoxyaniline (56 mg, 0.365 mmol) similar to Example 92 and isolated as a tan solid (21 mg, 26%). 1H NMR (CDCl3): 8.83–8.81 (m, 1H), 8.49–8.46 (m, 1H), 7.86–7.80 (m, 1H), 7.39–7.35 (m, 1H), 6.99 (s, 1H), 6.70 (s, 1H), 6.53 (d, J=2.4 Hz, 2H), 6.30 (t, J=2.3 Hz, 1H), 3.82 (s, 6H), 2.51 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:32]=[CH:31][C:13]4[C:14]5[N:18]([CH2:19][CH2:20][O:21][C:12]=4[CH:11]=3)[CH:17]=[C:16]([C:22]3[N:23]([CH:28]([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[N:26]=3)[N:15]=5)[CH:7]=[N:6]2)[CH2:2]1.[C:33]([Si:37]([CH3:43])([CH3:42])[O:38][CH2:39][CH:40]=O)([CH3:36])([CH3:35])[CH3:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:33]([Si:37]([CH3:43])([CH3:42])[O:38][CH2:39][CH2:40][N:1]1[CH2:2][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:32]=[CH:31][C:13]4[C:14]5[N:18]([CH2:19][CH2:20][O:21][C:12]=4[CH:11]=3)[CH:17]=[C:16]([C:22]3[N:23]([CH:28]([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[N:26]=3)[N:15]=5)[CH:7]=[N:6]2)[CH2:4]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C5CNC5)c4)cc2OCC3)n(C(C)C)n1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C5CN(CCO[Si](C)(C)C(C)(C)C)C5)c4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene in methylene chloride was added (tert-butyl-dimethyl-silanyloxy)-acetaldehyde and acetic acid followed by sodium triacetoxyborohydride. The reaction was stirred at room temperature for about 5 hours and quenched with 1N NaOH. Methylene chloride was added and the mixture was extracted 3 times with methylene chloride. The organic phases were combined, dried with MgSO4 and concentrated. The mixture was purified by flash chromatography (0-10% MeOH in DCM) to afford 8-(1-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-azetidin-3-yl}-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene MS (ESI+) 589.3, which was treated with acid to give 230. 1H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.36 (d, J=8.4, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 7.41 (d, J=8.3, 1H), 7.32 (d, J=1.6, 1H), 5.90-5.78 (m, 1H), 4.97 (quin, J=6.9, 1H), 4.52 (s, 4H), 4.47 (t, J=5.4, 1H), 3.73 (t, J=7.6, 2H), 3.47-3.37 (m, 4H), 2.58 (t, J=7.7, 2H), 2.25 (s, 3H), 1.47 (d, J=6.6, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(F)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 4-fluorobenzene-sulfonyl chloride (256 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12m as a solid (300 mg, 88.4%). HPLC: 86.16% (Rt=7.72 min).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH:7]2[N:9]([C:10](OCC3C=CC=CC=3)=O)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[C:20]1([Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O=[C:29]1[CH2:35][CH:34]2N(C(OC(C)(C)C)=O)[CH:31]([CH2:32][CH2:33]2)C1.[Li].BrC1C=CC=CC=1CO>>[CH2:10]([N:9]1[CH:4]2[CH2:5][CH2:6][CH:7]1[CH2:8][C:2]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:29]=1)([OH:1])[CH2:3]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CC2CCC(C1)N2C(=O)OCc1ccccc1
Agent: OCc1ccccc1Br
Agent: [Li]
Product: OC1(c2ccccc2)CC2CCC(C1)N2Cc1ccccc1

Procedure:
2.80 g of the entitled compound was obtained as a white powder in the same manner as in Production Example 8-3, for which, however, benzyl 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylate and phenylmagnesium bromide were used in place of tert-butyl 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylate and the lithium reagent prepared from and 2-bromobenzyl alcohol and n-butyllithium-hexane solution used in Production Example 8-3.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.N>O1CCCC1>[Br:1][C:2]1[O:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([NH2:22])=[O:19])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1c(-c2ccc(Br)o2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: NC(=O)Cn1c(-c2ccc(Br)o2)nc2cccnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.9 %

Procedure:
A mixture of 2-(5-bromo-2-furanyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.90 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5 hours with a stream of nitrogen bubbling through it. The reaction mixture was cooled in a dry ice/acetone bath, and liquid ammonia (50 ml) was added. The mixture was allowed to warm to room temperature and was stirred for 2 days under nitrogen atmosphere. The solvents were removed under reduced pressure and the resulting solid was triturated in water (100 ml), collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was recrystallized from hot methanol and dried under high vacuum at 40° C. to give 2.23 g (38%) of title compound, mp. >250° C.
Reaction SMILES: N[C@@H](CC1C=CC(OC[CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=CC=1)C(O)=O.C[O:30][C:31](=[O:49])[C@H:32]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1)[NH:33]C(OC(C)(C)C)=O.CC1OC(C2C=CC=CC=2)=NC=1CO>>[NH2:33][C@@H:32]([CH2:41][C:42]1[CH:43]=[CH:44][C:45]([O:48][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:46][CH:47]=1)[C:31]([OH:49])=[O:30]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: Cc1oc(-c2ccccc2)nc1CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
Amino acid Intermediate 54 was prepared as described for the preparation of Intermediate 46. From 187 mg of N-(Boc)-L-Tyrosine methyl ester and 120 mg of Intermediate 8D (with DIAD replacing DEAD) was prepared 116 mg (53% overall yield) of the title compound as a solid. 1H NMR (DMSO-d6, 300 MHz) δ7.89-7.85 (m, 2H), 7.43-7.36 (m, 3H), 7.12 (d, 2H, J=8.5), 6.9 (d, 2H, J=8.5), 4.9 (s, 2H), 3.63 (m, 1H), 3.0 (dd, 1H, J=14.4, 4.5), 2.85 (dd, 1H, J=14.4, 8.1), 2.37 (s, 3H); low resolution MS (ES+)m/e 353.07 (MH+).
Reaction SMILES: [CH3:1][I:2].[CH3:3][S:4][C:5]1[C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:8][S:7][N:6]=1>>[I-:2].[CH3:3][S:4][C:5]1[C:9]([C:10]2[CH:11]=[N+:12]([CH3:1])[CH:13]=[CH:14][CH:15]=2)=[N:8][S:7][N:6]=1
Reactant: CI
Reactant: CSc1nsnc1-c1cccnc1
Product: CSc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl iodide (1 ml, 15 mmol) was added to a solution of 3-(3-methylthio-1,2,5-thiadiazol-4-yl)pyridine (0.5 g, 2.3 mmol) and the reaction mixture was stirred at room temperature for 48 h and evaporated.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[H][H]>CO.[Pd]>[NH2:13][C:3]1[C:2]([NH2:1])=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(N)c([N+](=O)[O-])c(C(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(N)c(C(=O)O)c1
Yield: 51.2 %

Procedure:
3-amino-5-methoxy-2-nitrobenzoic acid (85; 1.6 g, 7.5 mmol) was dissolved in methanol (100 mL) and 10% Pd/C (300 mg) was added. The resulting reaction mixture was stirred under 1 atm of hydrogen at room temperature for 18 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford 2,3-diamino-5-methoxybenzoic acid 86 (0.7 g).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17](=[O:24])[C:18](=[CH:22][CH:23]=2)[C:19](O)=O)=[CH:11][CH:10]=1)(=[O:8])=[O:7].S(Cl)([Cl:28])=O>>[ClH:28].[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][C:17](=[O:24])[C:18](=[CH:22][CH:23]=2)[CH2:19][Cl:28])=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: CN(C)CCNS(=O)(=O)c1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reactant: O=S(Cl)Cl
Product: CN(C)CCNS(=O)(=O)c1ccc(-c2ccc(CCl)c(=O)[nH]2)cc1
Product: Cl

Procedure:
A suspension of 3.5 g. of 6-[4-[(2-dimethylaminoethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinic acid in 175 ml. of thionyl chloride is stirred at room temperature for 16 hours. The mixture is diluted with 300 ml. of hexane and the precipitate of 6-[4-[(2-dimethylaminoethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinyl chloride hydrochloride is collected by filtration, washed with hexane and dried. The acid chloride is used as such without further purification.
Reaction SMILES: [CH2:1]([CH:4]1[C:8](=[O:9])[O:7][S:6](=[O:11])(=[O:10])[CH2:5]1)[CH2:2][CH3:3].C(OCC(O)C)(=[O:16])C(C)=C.[CH3:22][CH:23]([O:31][C:32]([C:34]1[CH:39]=CC=C(S(O)(=O)=O)[C:35]=1C(O)=O)=[O:33])[CH2:24]OC(C(C)=C)=O>C1(C)C=CC=CC=1>[S:6]([CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[C:8]([O:7][C:23]([O:31][C:32](=[O:33])[C:34]([CH3:39])=[CH2:35])([CH3:24])[CH3:22])=[O:9])([OH:11])(=[O:16])=[O:10]
Reactant: C=C(C)C(=O)OCC(C)O
Reactant: CCCC1CS(=O)(=O)OC1=O
Reactant: C=C(C)C(=O)OCC(C)OC(=O)c1cccc(S(=O)(=O)O)c1C(=O)O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC(C)(C)OC(=O)C(CCC)CS(=O)(=O)O

Procedure:
178 g. of 4-n-propyl-1,2-oxathiolane-5-one 2,2-dioxide and β-hydroxypropyl methacrylate are reacted in toluene as described in procedure (7) (a) above to produce methacryloxyisopropyl 2-(sulfomethyl)-pentanoate.