Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[CH:6]([NH:9][CH2:10][CH2:11]O)([CH3:8])[CH3:7].C1(C)C=CC=CC=1>O>[S:1]([O:3][CH2:11][CH2:10][NH:9][CH:6]([CH3:8])[CH3:7])([OH:2])(=[O:5])=[O:4]
Reactant: CC(C)NCCO
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)NCCOS(=O)(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 50-ml three-necked flask, 1.01 g (10 mmol) of sulfuric acid (97%) was diluted with 1 g of water, and the resulting dilution was ice-cooled. A mixture of 1.03 g (10 mmol) of 2-isopropylaminoethanol and 1 g of water was slowly dropped into the cooled dilution. After completion of the dropping, the resulting mixture was warmed to room temperature and 10 ml of toluene was added thereto. The mixture thus obtained was dehydrated by heating with vigorous stirring after attaching a Dean-Stark trap to the flask. The mixture was heated and stirred for 4 hours until a theoretical amount of water was removed. Then, the reaction was continued for another 1 hour. After a large portion of the toluene was removed by decantation, the residual toluene was distilled off under reduced pressure to obtain a crude product of 2-isopropylaminoethyl hydrogensulfate, the desired compound, quantitatively.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:17]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19].CN1CCOCC1>C(Cl)Cl>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([C:17]([N:11]2[C:12]3[C:8](=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[C:14]([F:16])[CH:13]=3)[CH:9]=[CH:10]2)([CH2:22][CH3:23])[C:18]([O:20][CH3:21])=[O:19])=[CH:29][CH:28]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(N)cc(F)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cc(F)cc21
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.23 g, 2 mmol) was added to a stirred solution of methyl 2-(4-amino-6-fluoro-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (0.6 g, 1.7 mmol) and 4-methylmorpholine (0.25 g, 2.5 mmol) in DCM (8 mL) at 0° C. After 30 min, an additional portion of methanesulfonyl chloride (0.1 g, 1 mmol) was added. After 1 h, the reaction mixture was partitioned between DCM and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE: EA=2:1) to afford the title compound. LC/MS m/z=439.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH2:3][N:4]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][C:21]2=[O:30])[CH2:14][CH2:13]1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:30]=[C:21]1[CH:22]=[N:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]1[CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][CH:12]([NH:4][CH2:3][C:2]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:1])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N(CC(=O)Nc1ccccn1)C1CCN(CCn2c(=O)cnc3ccccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC1CCN(CCn2c(=O)cnc3ccccc32)CC1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To 3 mL of a dichloromethane solution containing 0.26 g of tert-butyl (2-oxo-2-(pyridin-2-ylamino)ethyl)(1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of trifluoroacetic acid was added and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, chloroform and water were added, and adjusted to pH 11 with 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 0.20 g of N2-(1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)-N-(pyridin-2-yl)glycinamide as a light brown oil.
Reaction SMILES: [CH2:1]=[C:2]([O:5][Si](C)(C)C)[CH:3]=[CH2:4].[CH3:10][S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:10][S:11]([CH:14]1[CH2:4][CH2:3][C:2](=[O:1])[CH2:5][CH2:15]1)(=[O:13])=[O:12]
Reactant: C=CS(C)(=O)=O
Reactant: C=CC(=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
A solution containing (buta-1,3-dien-2-yloxy)(trimethyl)silane (12.5 ml, 70.7 mmol) in toluene (50 ml), was treated with (methylsulfonyl)ethene (4.1 ml, 47.1 mmol) and heated under reflux for 76 hours. After which time, the reaction mixture was cooled to room temperature and concentrated in-vacuo to give a yellow oil. The oil was dissolved in CH2Cl2 (120 ml) and filtered through Celite®. The filtrate was concentrated in-vacuo and the resulting residue was then dissolved in MeOH (8 ml) with cooling (ice/water). It was then treated with TFA (2.0 ml). The reaction mixture was stirred at 0° C. for a further 10 minutes and then at room temperature for 25 hours. The reaction mixture was concentrated in-vacuo and the residue was purified by flash column chromatography (0-10% MeOH/CH2Cl2) 100 g SNAP cartridge on the Biotage Isolera to give the title compound 1.2 g (14%) as a thick yellow oil. LC-MS 94%, 0.39 min (3.5 minute LC-MS method), m/z=177.0 (ELS visible only). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 3.24-3.32 (m, 1H) 2.94 (s, 3H) 2.62-2.70 (m, 2H) 2.50-2.56 (m, 2H) 2.38-2.45 (m, 2H) 2.07-2.18 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[N:14]=[C:15]([CH3:19])[CH:16]=[C:17](O)[C:12]3=[CH:11][C:10]=2[CH3:20])=[C:5]([CH3:21])[CH:4]=1.P(Br)(Br)[Br:23].C([O-])(O)=O.[Na+]>BrC1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:23][C:17]1[C:12]2[N:13]([C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:21])=[C:10]([CH3:20])[CH:11]=2)[N:14]=[C:15]([CH3:19])[CH:16]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(-c2c(C)cc3c(O)cc(C)nn23)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Brc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2c(C)cc3c(Br)cc(C)nn23)c(C)c1
Temperature: 25 °C

Procedure:
A solution of 7-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrrolo[1,2-b]pyridazin-4-ol (0.16 g, 0.567 mmol) and phosphorus tribromide (0.27 mL, 2.83 mmol) in bromobenzene (3.0 mL) was refluxed for 5 h. After cooling down to room temperature, the mixture was diluted with CHCl3. Saturated NaHCO3 solution was added to neutralize and separated immediately. The aqueous layer was extracted with CHCl3 (2×). The combined CHCl3 solution was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (silica gel, 1/20 EtOAc/hexane) to afford 0.14 g (64%) of light yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=8 Hz, 1H), 6.82 (d, J=3 Hz, 1H), 6.76 (dd, J=3, 8 Hz, 1H), 6.59 (s, 1H), 6.49 (s, 1H), 3.79 (s, 3H), 2.28 (s, 3H), 2.12 (s, 3H), 1.98 (s, 3H); MS m/z 347.1 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:45][O:46][C:47]1[C:48]2[N:61]=[C:60]([NH2:62])[S:59][C:49]=2[C:50]([N:53]2[CH2:58][CH2:57][O:56][CH2:55][CH2:54]2)=[N:51][CH:52]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:62][C:60]1[S:59][C:49]2[C:50]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[N:51][CH:52]=[C:47]([O:46][CH3:45])[C:48]=2[N:61]=1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cc1OC

Procedure:
From 3,4-dimethoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 431 (M+H+, 100).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH2:9][CH:10]([C:12]([OH:14])=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15]I>O1CCCC1>[C:1]1([C:7]2[S:8][CH2:9][C:10]([CH3:15])([C:12]([OH:14])=[O:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: O=C(O)C1CSC(c2ccccc2)=N1
Solvent: C1CCOC1
Product: CC1(C(=O)O)CSC(c2ccccc2)=N1

Procedure:
Cysteine, benzonitrile, and 5 equivalents of triethylamine were refluxed in ethanol for 6-8 hours to obtain a 66-70% yield of 2-phenylthiazoline-4-carboxylic acid. The 2-phenylthiazoline-4 carboxylic acid was reacted with 2.05 equivalents of base and 1 equivalent of methyl iodide in tetrahydrofuran at 0° C. to form 2-phenyl-4-methylthiazoline-4 carboxylic acid. The 2-phenyl-4-methylthiazoline-4-carboxylic acid can be hydrolyzed with hydrochloride acid, thereby obtaining a mixture of (R)- and (S)-2-methylcysteine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][CH:3]=1.C[O-].[Na+].Cl.Cl.[NH2:17][C:18]1[C:23](N)=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25]>CO>[OH:25][C:19]1[C:18]2[NH:17][C:8]([CH2:7][O:6][C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9][C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: Nc1cccc(O)c1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1cccc2nc(COc3ccc(Cl)cc3)[nH]c12

Procedure:
In a 50 ml single neck round bottom flask, under a nitrogen atmosphere, 4-chlorophenoxyacetonitrile (0.46 g, 2.79 mmol) was admixed in methanol (11 ml). The contents were stirred to achieve dissolution. To this solution were added sodium methoxide (0.164 g, 3.0 mmol). The resulting mixture was stirred for about 40 minutes. To this mixture was added 2,3-diaminophenol dihydrochloride salt (0.5 g, 2.5 mmol) and the resulting mixture was stirred for two hours at room temperature. The reaction mixture was filtered and the filtrate was added to 60 ml of water. A light brown precipitate formed and this precipitate is removed by filtration, and washed with 20 ml of water. The solid was dried in a vacuum oven overnight.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH2:12].C(N(CC)CC)C.Cl[C:27]1[S:31][N:30]=[C:29]([O:32][CH3:33])[N:28]=1>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:17])[C@H:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:12][C:27]1[S:31][N:30]=[C:29]([O:32][CH3:33])[N:28]=1
Reactant: COc1nsc(Cl)n1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(C)C)Nc1nc(OC)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
A solution of N-L-leucyl-L-proline methyl ester hydrochloride (5.6 g, 20 mmol, prepared according to the procedure by Jones, J. B. et al. in J. Med. Chem. 1995, 38, 3078) and triethylamine (5.6 mL, 40 mmol) in DMF (60 mL) was stirred at room temperature for 15 min. Then, a solution of 5-chloro-3-methoxy-[1,2,4]thiadiazole (1.51 g, 10 mmol) in DMF (10 mL) and tetrabutylammonium bromide (150 mg) were added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with water and extracted into ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate, brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a mixture of hexane and ethyl acetate (7/3 and 6/4) afforded N-(3-methoxy-[1,2,4]thiadiazol-5-yl)-L-leucyl-L-proline methyl ester (1.92 g, 53.9%) as as an off-white foam. 1H-NMR (CDCl3) δ7.10 (d, J=8.5 Hz, 1H, NHCH), 4.74 (m, 1H, NHCH), 4.57 (dd, J=8.6, 4.6 Hz, 1H, CHCO2), 3.92 (s, 3H, OMe), 3.85 (m, 1H), 3.69 (s, 3H, OMe), 3.62 (m, 1H), 2.17-2.23 (m, 1H), 1.95-2.07 (m, 4H), 1.77-1.82 (m, 1H), 1.59-1.66 (m,1H), 0.97 (d, J=6.5 Hz, 3H, Me), 0.94 (d, J=6.7 Hz, 3H, Me); MS (m/z) 357 (M+ +1), 228, 200, 130, 101, 70.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([CH3:10])([CH3:9])[C:6](O)=[O:7])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.CN(C1C=CC=CN=1)C.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>C(Cl)Cl>[CH3:9][C:5]([CH3:10])([C:6]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:7])[C:4]([O:3][CH2:1][CH3:2])=[O:11]
Reactant: CS(N)(=O)=O
Reactant: CCOC(=O)C(C)(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)C(=O)NS(C)(=O)=O
Yield: 66.8 %

Procedure:
3-Ethoxy-2,2-dimethyl-3-oxopropanoic acid (100 mg, 0.624 mmole) was added to a stirring suspension of 2.5 equivalents of PS-DCC from Argonaut and 3 equivalents of dimethylaminopyridine in DCM. To this was added methanesulfonamide (41.6 mg, 0.437 mmole). The solution was filtered of and concentrated to give 69.3 mg of ethyl 2,2-dimethyl-3-[(methylsulfonyl)amino]-3-oxopropanoate (67% yield crude). MS ES− 236 (M−H). 1H NMR (300 MHz, Chloroform-d) δ ppm 1.4 (t, J=6.7 Hz, 3H), 1.6 (s, 6H), 3.3 (m, 3H), 4.3 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1)=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C(O)C>[N:15]1[C:3]([C:5]2[CH:6]=[CH:7][C:8]3[S:12][C:11](=[O:13])[NH:10][C:9]=3[CH:14]=2)=[CH:2][N:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=12
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccc2sc(=O)[nH]c2c1
Solvent: CCO
Product: O=c1[nH]c2cc(-c3cn4ccccc4n3)ccc2s1
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
A solution of 5-bromoacetyl-2-benzothiazolinone (3.3 g) and 2-aminopyridine (4.2 g) in ethanol was refluxed for 5 hours and the reaction mixture was evaporated in vacuo. To the residue was added a mixture of water and ethyl acetate and the resulting mixture was acidified to pH 1.0 with 10 % hydrochloric acid. The precipitate was collected by filtration and added to a solution of saturated aqueous sodium bicarbonate. The mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with water and recrystallized from aqueous ethanol to give 5-(imidazo[1,2-a]pyridin-2-yl)-2-benzothiazolinone (0.24 g). mp>270° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]O[CH2:39][CH2:38]1.IC(CC)C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH:37]([CH3:41])[CH2:38][CH3:39])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: C1CCOC1
Agent: CCC(C)I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC(C)C(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 51.2 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), 2-iodobutane (0.115 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.108 g (51%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:29](O)=[O:30])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[N:39]1[CH2:44][C@H:43]([CH3:45])[CH2:42][C@H:41]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:49]([O:48][C:47]([NH:46][C@H:41]1[CH2:42][C@@H:43]([CH3:45])[CH2:44][N:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH:32][C:29]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:19]=3)[N:14]=2)=[O:30])[CH2:40]1)=[O:53])([CH3:50])([CH3:51])[CH3:52]
Reactant: O=C(Nc1cc2ccc(N3CCCCC3=O)cc2nc1C(=O)O)OCc1ccccc1
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCCCC4=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-(2-oxopiperidin-1-yl)quinoline-2-carboxylic acid (0.015 g, 0.036 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-yl]carbamate (0.013 g, 0.043 mmol) and HATU (0.034 g, 0.089 mmol) in DMF (0.3 mL), DIPEA (0.019 mL, 0.11 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The resulting layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure, then purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 60 mL/min.) to afford the sub-title compound (0.005 g, 20%). LCMS calc. for C39H46N7O6 [M+H]: m/z=708.3. found: 708.4.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH2:9].[CH:19]([O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)([CH3:21])[CH3:20]
Reactant: O=C1CCNCC1
Reactant: CC(C)Oc1cccc(CBr)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cccc(CN2CCC(=O)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-piperidone hydrochloride monohydrate (19.52 g, 127.12 mmol), 1-Bromomethyl-3-isopropoxy-benzene (19.41 g, 84.76 mmol) and K2CO3 in DMF (150 mL) is stirred at rt for 16 hr. Solvent is removed in vacco, the residue is extract (EtOAc/Brine), dried (Na2SO4), concentrated, and purified by chromatography (silica gel, EtoAc/hexanes, 2/3) to afford 14-4. (MH+, 266)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]1.Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:18][CH2:17][CH2:16][CH2:15][N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:22]=3[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:7][C:2]=2[F:1])[N:10]=[N:11]1
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Reactant: O=c1n(CCCF)nnn1-c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(-n2nnn(CCCF)c2=O)c(F)c1
Yield: 27.5 %

Procedure:
By the method Example 1, Step I, 0.85 g (0.0033 mole) of 1-(2-fluoro-4-hydroxyphenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one and 1.21 g (0.0050 mole) of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate (Example 1, Step H) were reacted in the presence of 0.70 g (0.0050 mole) of anhydrous potassium carbonate in 60 mL of N,N-dimethylformamide, yielding 0.42 g of methyl 2-[2-[4-[1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-on-1-yl]-3-fluorophenoxymethyl]-5-methylphenoxy]propionate as an oil. The NMR spectrum was consistent with the proposed structure. NMR: 1.64 (d, 3H, JHH =8 Hz); 2.2-2.4 (m, 2H); 2,32 (s, 3H); 3.72 (s, 3H); 4.18 (t, 2H, JHH =8 Hz); 4.50-4.64 (dt, 2H, JHH =8 Hz, JHF =45 Hz); 4.84 (q, 1H, JHH =8 Hz), 5.20 (q, 2H, JHH =8 Hz); 6.58-7.40 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[K+].[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH-:37])(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26]>CS(C)=O>[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:37][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:3]=2)(=[O:36])=[O:35])=[N:32][CH:33]=1)([CH3:27])[CH3:26]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1Cl
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Yield: 99.2 %

Procedure:
A solution of 3.5 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine and 4.98 g of 5-isopropyl-2-pyridine sulfonamide potassium salt (Example 1, section e) in 40 ml of DMSO was stirred at room temperature for 4 h. The mixture was poured onto water and extracted twice with diethyl ether. The aqueous layer was acidified with acetic acid. The precipitate that formed was collected, washed with water and diethyl ether and dried to furnish 5.1 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimi-dinyl]-2-pyridine sulfonamide as a white solid. LC-MS: tR=4.87 min, [M+1]+=513.32, [M−1]−=511.26.
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([O:14]C)[C:9]([O:16][CH3:17])=[CH:8][CH:7]=1.O>ClCCl>[F:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([OH:14])[C:9]([O:16][CH3:17])=[CH:8][CH:7]=1
Reactant: COc1ccc(F)c(C=O)c1OC
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(F)c(C=O)c1O
Yield: 95.1 %

Procedure:
1M boron trichloride in dichloromethane (25 ml; 25 mmol) was added to a solution of 6-fluoro-2,3-dimethoxy-benzaldehyde [Cantrell, Amanda S.; Engelhardt, Per; Hoegberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; et al.; J.Med.Chem.; 39; 21; 1996; 4261-4274] (4.26 g; 23 mmol) in dichloromethane (30 ml) keeping the reaction temperature at −70 C. The reaction mixture stirred at room temperature overnight and hydrolyzed with water. The organic phase was separated, washed with water and evaporated in vacuo. The residue was chromatographed (silica gel, EA:Hex, 5:1) to give 3.72 g (94%) of 6-fluoro-2-hydroxy-3-methoxy-benzaldehyde as yellow crystals.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=1.CC1C=CC=C(C)C=1C1C=CC(C([N:38]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[CH2:42][N:41]3[C:49]([C:52]([NH:54][CH2:55][C:56]4[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=4)=[O:53])=[CH:50][CH:51]=[C:40]3[CH2:39]2)=O)=CC=1>N1C=CC=CC=1>[CH3:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]([N:38]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[CH2:42][N:41]3[C:49]([C:52]([NH:54][CH2:55][C:56]4[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=4)=[O:53])=[CH:50][CH:51]=[C:40]3[CH2:39]2)=[O:21])=[CH:17][CH:18]=1
Reactant: CSc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CSc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reaction time: 1 h

Procedure:
To 20 mL of thionyl chloride was added 0.244 g (0.001 mol) of 2′-(methylthio)-1,1′-biphenyl-4-carboxylic acid of Step A. The solution was heated under reflux for 1 hour. The excess thionyl chloride was removed in a vacuo. To the residue was added 25 mL of dry pyridine and 0.318 g (0.001 mol) of N-(pyridyl-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 12. The reaction was allowed to stand at room temperature for 1 hour and the pyridine was removed in vacuo. The residue was collected and washed with water giving a tan solid (0.62 g), m.p. 172-175° C.