Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CCCCCCCC.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26].Cl>[Fe](Cl)(Cl)Cl.O.C(OC(=O)C)C>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25]([C:4]1[C:5]([CH3:13])=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])=[O:26]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CCCCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)c(OC)c1OC
Temperature: 105 °C

Procedure:
A mixture of 3,4,5-trimethoxytoluene (9.11 g; 50 mmol), octane (25 ml) and iron(III)chloride (50 mg) is stirred at 105° C., and percolating nitrogene 2,6-dichlorobenzoylchloride (12.04 g; 57.5 mmol) is added dropwise within 15 minutes. The mixture is kept at 105° C. and stirred for another 15 minutes. After cooling to 50° C. ethylacetate (50 ml) is added, the mixture shaken twice with 2N hydrochloric acid, once with water and dried. The ethylacetate is evaporated (70° C.) and the liquid cooled with stirring. At 50° C. petrolether (50 ml) is added. The white crystalls formed are sucked off, washed with petrolether and dried. Yield 12.55 g (70.7%), mp. 92° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C1COCC1>[O:35]1[CH2:36][CH2:37][CH:32]([NH:31][C:12]2[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:30])[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=2)[CH2:33][CH2:34]1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: NC1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC2CCOCC2)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 18 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and 4-aminotetra-hydropyran (102 mg, 1 mmol) were combined in THF (10 mL) and stirred under Ar at 23° for 18 h. The solvents were removed in vacuo, and the residue was flash chromatographed with 0-15% EtOAc/CH2Cl2. Recrystallization from CH2Cl2/hexane gave the title compound as a light-yellow crystalline solid. mp 211-212°, LC MS m/z=449 (MH+) Retention time=2.21 min
Reaction SMILES: CN(C)CCCN=C=NCC.[NH2:12][C:13]1[C:14](=[O:26])[N:15]([CH3:25])[C:16](=[O:24])[N:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:18]=1[NH2:19].[CH3:27][O:28][C:29]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[C:35]2[C:30]=1[C:31]([CH2:41][C:42](O)=O)=[CH:32][N:33]=[CH:34]2.ON1C2C=CC=CC=2N=N1>ClCCl.O>[CH2:20]([N:17]1[C:18]2[N:19]=[C:42]([CH2:41][C:31]3[C:30]4[C:35](=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:29]=4[O:28][CH3:27])[CH:34]=[N:33][CH:32]=3)[NH:12][C:13]=2[C:14](=[O:26])[N:15]([CH3:25])[C:16]1=[O:24])[CH:21]([CH3:22])[CH3:23]
Reactant: COc1ccc2cncc(CC(=O)O)c2c1OC
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)c2c1OC
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (20.6 ml, 0.1 mol) is added to a mixture of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (20 g, 0.094 mol), (5,6-dimethoxy-isoquinolin-4-yl)-acetic acid (26.7 g, 0.094 mol), and 1-hydroxybenzotriazole (19.2 g, 0.142 mol) in 1:1 dichloromethane-water (400 ml). The reaction is stirred at ambient temperature for 4.5 hours and the resultant solid collected by filtration. Slurrying in water (500 ml), filtration and washing with water (250 ml) followed by drying, further trituration with methanol and drying gives an intermediate together with slightly less pure material from concentration of the methanol triturate. The intermediate (16.08 g) is dissolved in water (100 ml) and methanol (100 ml) followed by the addition of 4M aqueous sodium hydroxide (56 ml) and the resultant solution is heated at 70° C. over night. After cooling to ambient temperature, the methanol is evaporated and the residue acidified to pH 1 with concentrated hydrochloric acid. The resultant hydrochloride salt is collected by filtration and dried. The product is then be converted to the free base by treatment with aqueous sodium hydroxide to pH 11 and washing with water to afford 3-isobutyl-8-(5,6-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3,7-dihydro-purine-2,6-dione [MH]+ 424.6.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)#N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:22]([NH:24][CH2:25][CH2:26][NH2:27])[CH3:23].[O-]CC.[Na+]>C(O)C>[CH2:22]([N:24]1[CH2:25][CH2:26][N:27]=[C:1]1[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:23]
Reactant: CCNCCN
Reactant: N#CCCc1ccncc1
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Product: CCN1CCN=C1CCc1ccncc1
Temperature: 190 °C
Yield: 59.1 %

Procedure:
A mixture of 4-(2-cyanoethyl)pyridine (1.32 g, 0.01M) and N-ethyl-1,2-diaminoethane mono-p-toluenesulfonate (5.5 g, 0.02M) were heated at 190° C. for 4 hrs under nitrogen. The reaction mixture was dissolved in ethanol (30 ml) and sodium ethoxide (0.02M) in ethanol (50 ml) was added. The mixture was filtered and the filtrate was stripped to dryness and distilled at 130° C./0.2 mmHg to yield 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-pyridine (1.2 g, 60% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]=[CH:13][C@H:12]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1>ClCCCl>[CH2:19]([O:18][C:16]([C@H:12]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:15][C@H:14]2[C@H:13]1[O:34]2)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)[C@@H]1C=CCN1C(=O)OCc1ccccc1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)[C@@H]1[C@@H]2O[C@H]2CN1C(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
Were prepared according to the procedure described in Tetrahedron, 1998, 54, 981-986 from (S)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid dibenzyl ester. To a solution of (S)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid dibenzyl ester (7.5 g, 22.23 mmol) in DCE (80 mL) were added mCPBA (7.67 g, 44.5 mmol) and 4,4′-thiobis(6-tert-butyl-m-cresol) (0.797 g, 2.22 mmol). The reaction mixture was then heated to 90° C. overnight. Then was concentrated. The crude residue was diluted in CH2Cl2 (200 mL) and washed with an aq. solution of Na2S2O5 5% and with a sat. aq. solution of NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 10:0 to 8:2) give (1S,2S,5S)-6-oxa-3-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid dibenzyl ester: MS (UPLC/MS): 354 [M+H]+, tR (HPLC conditions b): 2.24 min and (1S,2S,5R)-6-oxa-3-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid dibenzyl ester: MS (UPLC/MS): 354 [M+H]+, tR (HPLC conditions b): 2.15 min.
Reaction SMILES: C([CH:3]1[CH2:29][CH2:28][CH2:27][CH:26]2[N:4]1[C:5](=[O:72])[C:6](=[O:71])[C:7]1([OH:70])[O:66][CH:11]([CH:12]([O:64][CH3:65])[CH2:13][CH:14]([CH3:63])[CH2:15][C:16]([CH3:62])=[CH:17][CH2:18][C:19](=[O:61])[CH2:20][CH:21]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55])[CH:22]([CH3:52])[CH:23]([C:31]([CH3:51])=[CH:32][CH:33]3[CH2:38][CH2:37][CH:36]([O:39][CH2:40][CH:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[OH:42])[CH:35]([O:49][CH3:50])[CH2:34]3)[O:24][C:25]2=[O:30])[CH:10]([O:67][CH3:68])[CH2:9][CH:8]1[CH3:69])C.C[N+]1([O-])CCO[CH2:76][CH2:75]1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:75]([CH:18]1[CH:17]=[C:16]([CH3:62])[CH2:15][CH:14]([CH3:63])[CH2:13][CH:12]([O:64][CH3:65])[CH:11]2[O:66][C:7]([OH:70])([CH:8]([CH3:69])[CH2:9][CH:10]2[O:67][CH3:68])[C:6](=[O:71])[C:5](=[O:72])[N:4]2[CH:26]([CH2:27][CH2:28][CH2:29][CH2:3]2)[C:25](=[O:30])[O:24][CH:23]([C:31]([CH3:51])=[CH:32][CH:33]2[CH2:38][CH2:37][CH:36]([O:39][CH2:40][C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:42])[CH:35]([O:49][CH3:50])[CH2:34]2)[CH:22]([CH3:52])[CH:21]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:55])[CH3:56])[CH2:20][C:19]1=[O:61])[CH3:76]
Reactant: CCC1CCCC2C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC(=O)CC=C(C)CC(C)CC(OC)C3OC(O)(C(=O)C(=O)N12)C(C)CC3OC
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Yield: 77.1 %

Procedure:
To solution of 17 ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2"'-phenyl-2"'hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (13 mg in 0.3 mL methylene chloride) was added powdered 4A molecular sieves (10 mg), 4-methylmorpholine N-oxide (6.0 mg), tetrapropylammonium perruthenate (1.0 mg) and the reaction stirred at room temperature. After 30 minutes the mixture was filtered through a small diatomaceous earth/silica gel plug and the filtrate concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (10 mg).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7](S(Cl)(=O)=O)=[CH:6][CH:5]=1)([O-])=O.[CH2:14]([N:16](C(C)C)C(C)C)C.[OH:23][C@H:24]([CH2:49]NCC(C)C)[C@@H:25]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34]C2C=CC=CN=2)=[CH:29][CH:28]=1>ClCCl>[C:14]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:4]=1)[CH2:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C@H:25]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])[C@H:24]2[CH2:49][O:23]2)=[CH:32][CH:31]=1)#[N:16]
Reactant: CC(C)CNC[C@@H](O)[C@H](Cc1ccc(OCc2ccccn2)cc1)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2cccc(C#N)c2)cc1)[C@H]1CO1

Procedure:
To a stirred solution of the product from the previous step (0.42 g, 0.96 mmol) in 20 mL of anhydrous dichloromethane were added 4-nitrobenzenesulfonyl chloride (0.25 g, 1.1 mmol) and N-ethyldiisopropylamine (0.15 g, 1.7 mmol) The mixture was allowed to react for the given number of hours [1] and at which time the solvent was removed under reduced pressure. The residue was redissolved in dichlormethane and extracted with water (3×50 mL). The organic phase was dried with magnesium sulfate, filtered, and removed under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes [2] as eluent to provide the following compounds [Y:(3)]:
Reaction SMILES: [C:1]([Si:5]([C:8]#[CH:9])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].Br[C:11]1[C:16]([F:17])=[CH:15][C:14]([Br:18])=[CH:13][N:12]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[Br:18][C:14]1[CH:15]=[C:16]([F:17])[C:11]([C:9]#[C:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[N:12][CH:13]=1
Reactant: C#C[Si](C)(C)C(C)(C)C
Reactant: Fc1cc(Br)cnc1Br
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)C#Cc1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under an argon atmosphere, 2.62 mL (13.811 mmol) of tert-butylethynyldimethylsilane was added to a solution of 3.20 g (12.56 mmol) of 2,5-dibromo-3-fluoropyridine, 5.22 mL of triethylamine (37.67 mmol), 59.8 mg (0.31 mmol) of CuI, and 220.3 mg (0.31 mmol) of bis(triphenylphosphane)palladium (II) chloride in 30 mL of absolute THF at 15° C. and the mixture was stirred for 2 hours at RT. 1 mL of tert-butylethynyldimethylsilane was added and the mixture was again stirred for 1 hour at RT. The reaction mixture was evaporated down in vacuo and the residue was taken up in EtOAc. The organic phase was washed with semisaturated aqueous sodium bicarbonate solution, 5% aqueous ammonia, and water, dried over magnesium sulfate, and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, PE/DCM 9:1). Yield: 1.62 g (41% of theoretical); C13H17BrFNSi (M=314.269); calc.: molpeak (M+H)+: 314/316 (Br); found: molpeak (M+H)+: 314/316 (Br); HPLC-MS: 7.85 minutes (method B).
Reaction SMILES: C[N:2]([CH:4]=O)[CH3:3].P(Cl)(Cl)([Cl:8])=O.[F:11][CH:12]([F:20])[C:13]1[CH2:17][C:16](=[O:18])N(C)[N:14]=1>>[Cl:8][C:4]1[N:2]([CH3:3])[N:14]=[C:13]([CH:12]([F:20])[F:11])[C:17]=1[CH:16]=[O:18]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Reactant: CN1N=C(C(F)F)CC1=O
Product: Cn1nc(C(F)F)c(C=O)c1Cl
Temperature: 120 °C
Yield: 78.2 %

Procedure:
DMF (9.5 mL, 0.12 mol) was stirred over ice bath and phosphoryl chloride (24.0 mL, 0.257 mol) was added dropwise. To the solution was added 3-(difluoromethyl)-1-methyl-1H-pyrazol-5(4H)-one (5.51 g, 0.0372 mol) portion wise and the mixture was heated at 120° C. for 40 minutes. The reaction mixture was cooled, and the phosphoryl chloride was quenched by adding small chunks of ice slowly with stirring. The mixture was then extracted with ethyl acetate three times and combined organic layer was washed with water and brine, dried over MgSO4 and evaporated to give 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (5.66 g, 78.2%) as a dark orange/brown solid. This material was used without further purification for the next reaction.
Reaction SMILES: [F:1][CH:2]1[CH:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[F:1][C@H:2]1[C@H:7]([O:8][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(F)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)[C@H](F)C1
Temperature: 0 °C
Reaction time: 14 h
Yield: 10.1 %

Procedure:
A solution of tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (52.76 g, 241 mmol) dissolved in anhydrous methylene chloride (1 L) was cooled to 0° C. and treated with triethylamine (43.6 mL, 313 mmol) followed by methanesulfonyl chloride (20.5 mL, 265 mmol). The solution was allowed to warm slowly to ambient temperature and stirred for 14 hours. The mixture was partitioned between saturated NaHCO3 (400 mL) and methylene chloride (400 mL). The aqueous layer was extracted with methylene chloride. The combined organic phases were washed with 1N HCl and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexanes:EtOAc to provide the desired product (7.24 g).
Reaction SMILES: C[Li].C([O:5][CH2:6][CH3:7])C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21]C(N(OC)C)=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.O>O1CCCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:6](=[O:5])[CH3:7])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CCOCC
Reactant: CON(C)C(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
A solution of methyllithium in diethyl ether (40 mL, 44 mmol) was diluted with tetrahydrofuran (120 mL), and a solution of 2-(4′-bromobiphenyl-4-yl)-N-methoxy-N-methylacetamide (12 g, 37 mmol) in tetrahydrofuran (50 mL) was added at −78° C., followed by stirring at the same temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.50 (hexane/ethyl acetate=4/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (7.6 g, 26 mmol) as a white solid (yield 71%).
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.C1(C2C3C=CC=CC=3N([CH2:57][C:58](C3CC3)=[O:59])C(=O)N(CC(O)=O)N=2)CCCCC1.C(OC(=O)CSC1C=CC=C(N)C=1)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:58]([O:59][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:57]
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CC2)C1=O
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)CSc1cccc(N)c1
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except [5-cyclohexyl-1-(2-cyclopropyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 119, step a) and (3-amino-phenylsulfanyl)-acetic acid ethyl ester were used instead of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.90 (1H, br s), 8.44 (1H, s), 7.49 (3H, m), 7.29 (2H, m), 7.19 (1H, t), 7.08 (2H, t), 4.81 (1H, d), 4.56 (1H, d), 4.22 (2H, m), 3.65 (2H, s), 2.79 (1H, m), 2.01-1.68 (7H, m), 1.26 (4H, m), 1.09 (2H, m), 0.93 (2H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 55.42; H, 6.74; N, 8.42%; C29H32N4O5S.C7H17NO5.1.8H2O.0.4C4H8O2 requires: C, 55.65; H, 6.93; N, 8.63%.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:10](OCC)=[O:11].C(O)C>O.CCCCCC>[OH:11][CH:10]=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7]
Reactant: O=C1CCCCC1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: O
Product: O=C1CCCCC1=CO
Reaction time: 20 h
Yield: 126 %

Procedure:
Cyclohexanone (200 grams, 2.0 moles) is added dropwise over a period of 2.75 hours to a stirred mixture of sodium hydride (50% oil dispersion, 105 grams, 2.1 moles), ethyl formate (200 grams, 2.7 moles), anhydrous ethanol (5 ml) and hexane (3500 ml) at 20° C. under nitrogen. Stirring is continued at room temperature for an additional 20 hours at which time a quantity of water sufficient to dissolve the reaction mixture is added. The layers are separated and the organic phase is washed twice with 5% aqueous sodium hydroxide. The combined aqueous phases are acidified with 25% aqueous sulfuric acid, and extracted three times with hexane. The organic phase is then washed twice with water, and distilled through a 4" vigreaux column at a 1:1 reflux take off ratio from 1 g hydroquinone to yield 318 g (63% theory)2-hydroxymethylenecyclohexanone. Bp 47°-48° C. @ 0.5 mm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([OH:22])=O)[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.[NH4+].[Cl-].C[N:35](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH2:35])=[O:22])[CH2:17][CH2:18]3)[CH:12]=2)=[CH:4][C:3]=1[C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1ncc(-c2cnn(C3CCN(CC(=O)O)CC3)c2)cc1-c1nc2ccccc2s1
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of {4-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-piperidin-1-yl}-acetic acid (10.0 mg, 0.0184 mmol), NH4Cl (2.0 mg, 0.037 mmol), TBTU (8.86 mg, 0.0276 mmol) and DMF (1 mL) was charged with DIPEA (0.03 mL, 0.2 mmol) and allowed to stir at rt for 10 min. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=2.17-2.35 (m, 4H), 2.69 (td, J=11.9, 2.5 Hz, 2H), 3.28 (d, J=12.4 Hz, 2H), 3.37 (s, 2H), 4.29-4.40 (m, 1H), 7.41-7.47 (m, 1H), 7.53 (td, J=7.6, 1.3 Hz, 1H), 7.89 (s, 1H), 8.01 (dd, J=12.3, 8.0 Hz, 2H), 8.11 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.32 (d, J=2.3 Hz, 1H).
Reaction SMILES: [Br:1]Br.[N:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.O>C(O)C>[Br:1][C:12]1[CH:13]=[CH:14][C:9]([N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[CH:10][CH:11]=1
Reactant: c1ccc(N2CCOCC2)cc1
Reactant: BrBr
Solvent: CCO
Solvent: O
Product: Brc1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
Bromine (10.8 g, 67.4 mmol) was added to a solution of 4-(4-morpholinyl)benzene (10.0 g, 61.3 mmol) in ethanol (100 mL) at 0° C., and the mixture was stirred for 1 hour at room temperature. Water (100 mL) was poured into the reaction mixture, which was then extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate and water, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (10.7 g, yield 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[NH:8][CH2:7][C:6]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][C@@H:30]1[O:32][CH2:31]1>CC(C)=O.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[N:8]([CH2:28][CH2:29][C@H:30]3[CH2:31][O:32]3)[CH2:7][C:6]=2[CH:20]=1
Reactant: O=S1(=O)NCc2cc(F)ccc2N1c1ccccc1F
Reactant: BrCC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=S1(=O)N(CC[C@H]2CO2)Cc2cc(F)ccc2N1c1ccccc1F
Temperature: 45 °C
Reaction time: 14 h
Yield: 160 %

Procedure:
A solution 6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.13 g, 0.29 mmol) in acetone (3 mL) was treated with potassium carbonate (0.11 g, 0.81 mmol), (S)-(−)-4-Bromo-1,2-epoxybutane (0.14 mL, 1.41 mmol) and was heated to 45° C. for two h then at room temperature for 14 h. The reaction mixture was diluted with ethyl ether (40 mL) and washed with sat. sodium bicarbonate (2×20 mL), the organic layer was isolated, dried with MgSO4 and evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/heptane) to provided 6-fluoro-1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.17 g, 67%) as a white solid.