Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH2:10][CH2:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.BrBr.Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C2=C(C#N)CCS2)cc1
Agent: Br
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(-c2sccc2C#N)cc1
Yield: 64.4 %

Procedure:
49.9 g of 2-(4-methylphenyl)-3-cyano-4,5-dihydrothiophene, prepared in D), are dissolved in 200 ml of carbon tetrachloride, the mixture is heated to reflux and, after two hours, 11 g of bromine, dissolved in 200 ml of carbon tetrachloride, are added dropwise. Refluxing is continued until evolution of hydrobromic acid has ceased, and the solvent is evaporated off under vacuum. The residue is taken up in 200 ml of anhydrous tetrahydrofuran, and 28 g of potassium tert-butylate are added. The mixture is heated to reflux for one hour, then cooled and treated with water and sodium chloride and extracted with ether. The organic phase is evaporated under vacuum to give 31.8 g of 2-(4-methylphenyl)-3-cyanothiophene in the form of an oil, which is used without further purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=2)[CH:17]=1.C1N=C[N:30](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:30])=[O:23])=[CH:20][N:19]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(N)=O)cn2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 6-(4-(4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (69 mg, 0.189 mmol) in DMF (3 mL) was added CDI (37 mg, 0.227 mmol) and the resulting mixture stirred at 60° C. for 1 h. After cooling to room temperature ammonium hydroxide (300 μL, 1.9 mmol) was added and reaction mixture was stirred for 1 h and then evaporated. Purification by chromatography (reverse phase HPLC) afforded the title compound (56 mg, 81%) as a white foam. MS: m/e=364.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[F:33][C:34]([CH3:39])([CH3:38])[C@H:35]([NH2:37])[CH3:36].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[F:33][C:34]([CH3:39])([CH3:38])[C@H:35]([NH:37][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=1)=[O:23])[CH3:36]
Reactant: C[C@@H](N)C(C)(C)F
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(C)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 66.6 %

Procedure:
A 10 ml round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.27 mmol) and (R)-2-fluoro-1,2-dimethyl-propylamine hydrochloride (crude from Step 3, 155 mg, 0.55 mmol). DMF (1.2 ml) was added followed by N,N-diisopropylethylamine (0.20 ml, 1.15 mmol) and HATU (114 mg, 0.30 mmol). The reaction mixture was stirred at room temperature for 5 h. Water was added and the resultant suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 95 mg (66%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-fluoro-1,2-dimethyl-propyl)-amide as a light brown powder.
Reaction SMILES: [CH:1]1([CH:5]2[CH:10]=[CH:9][N:8]([C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[CH:7]=[CH:6]2)[CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Oc1ccccc1)N1C=CC(C2CCC2)C=C1
Agent: [Pd]
Solvent: CO
Product: O=C(Oc1ccccc1)N1CCC(C2CCC2)CC1
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Charge a 500 mL Parr reactor bottle with 10% palladium on carbon (0.56 g, 0.53 mmol) and purge with N2. Wet the catalyst with MeOH (50 mL) and add phenyl 4-cyclobutylpyridine-1(4H)-carboxylate (5.6 g, 21.9 mmol) and an additional 150 mL MeOH. Seal the bottle, purge four times with nitrogen, then four times with hydrogen. Pressurize with hydrogen gas (31 psi) and shake at ambient temperature for two hours. Vent the mixture, purge four times with nitrogen, filter the mixture; collect the filtrate; and then concentrate to remove the MeOH. Purify the crude material with silica gel flash column chromatography eluting with 10% EtOAc in hexane. Concentrate the fractions to give the title compound (2.93 g, 51.5%). MS (m/z): 260.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C@@H:10]([OH:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:26]1[CH:27]=[C:28]([CH2:32][O:33][CH2:34][CH2:35][CH3:36])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[CH:26][CH:27]=3)=[CH:19][CH:18]=2)[C@@H:10]([OH:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1c1ccc(O)cc1
Reactant: CCCOCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 26 h

Procedure:
A solution of 11.8 g (35.0 mmol) of (3R,4R,5S)-5-ethoxy-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylic acid tert-butylester in 40 ml of dimethylformamide was treated in succession with 10.3 g (45.0 mmol) of 3-bromo-propoxymethyl-benzene and 8.29 g (60.0 mmol) of potassium carbonate. This mixture was stirred at 120° C. for 26 hours. Subsequently, it was filtered, concentrated to a few milliliters, poured into 300 ml of an ice/water mixture and extracted three times with 100 ml of dichloromethane each time. The combined organic phases were washed once with a small amount of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The resulting crude product was separated on silica gel using a mixture of dichloromethane and methanol as the eluent and yielded (3R,4R,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-hydroxy-piperidine-1-carboxylic acid tert-butylester as colorless oil; MS: 486 (M+H+); 508 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[CH3:10][O:9][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH:19]=[O:20]
Reactant: CN(C)C=O
Reactant: COc1cncc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cncc(OC)c1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
To a solution of 3,5-dimethoxypyridine (3.6 g, 25.90 mmol, 1 eq.) in THF (80 mL) was added BuLi (3M/hexanes, 13.0 mL, 38.85 mmol, 1.5 eq.) at −20° C. The mixture was warmed to 0° C., stirred at 0° C. for 30 min, cooled back down to −78° C., and added DMF (3.8 g, 51.8 mmol, 2 eq.). The mixture was gradually warmed to 0° C., quenched with NH4Cl(sat) solution, and diluted with EtOAc. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-dimethoxyisonicotinaldehyde (2.7 g, 62%) as a yellow solid. LRMS (M+H+) m/z 168.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27]S(C)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.NCC1C(=O)NC(C)=CC=1CC>O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH2:24][CH3:27])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1
Reactant: CS(C)=O
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: CCc1cc(C)[nH]c(=O)c1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Product: CCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in DMSO (3 mL for 1 mmol), PyBOP (1.5 equiv.) was added and reaction stirred at room temperature for 15 min. Then 3-(aminomethyl)-4-ethyl-6-methylpyridin-2(1H)-one (2 equiv.) was added and reaction stirred overnight. On completion, water was added and solid that precipitates out was filtered and washed with water. Then this solid was stirred with acetonitrile for 10 min and filtered again to obtain the desired intermediate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([CH2:9][OH:10])[NH:7]1)=[O:5])[CH3:2].[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH:8]([CH2:9][O:10][Si:15]([C:12]([CH3:14])([CH3:13])[CH3:11])([CH3:17])[CH3:16])[NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1N[C@@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1NC1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
In a flame dried flask equipped with a magnetic stirring rod and a rubber septum with a N2 inlet was added (S,S) 3-hydroxymethylaziridine-2-carboxylic acid ethyl ester (296 mg, 2.04 mmol) and 12 ml of CH2Cl2. The reaction vessel was cooled to 0° C. then TBDMSCl (377 mg, 2.50 mmol) and DMAP (623 mg, 5.1 mmol) was added. The reaction was allowed to stir for 1 hour at 0° C. then at room temperature until the reaction was completed according to TLC (Rf=0.65; 7:3 hexanes/EtOAc). The reaction was diluted with CH2Cl2 then water was added. The organic layer was extracted three times, and the combined organic layers were washed first with saturated NaHCO3, then water, then brine and dried over solid Na2SO4. The mixture was filtered and dried under reduced pressure to afford a pale yellow oil, which was subjected to flash column chromatography (silica gel; 8:2 hexanes/EtOAc) to afford the title compound as a thick colourless oil in 99% yield. 1H NMR (CDCl3, 400 MHz) δ: 4.21 (q, J=3.6 Hz, 2H), 3.66 (dd, J=11.2 Hz, 5.2 Hz, 1H), 3.56 (dd, 10.8 Hz, 4.8 Hz, 1H), 2.42 (m, 2H), 1.37 (bt, 1H), 1.29 (t, J=7.2 Hz, 3H) ppm. 13C NMR (CDCl3, 100 MHz) δ: 172.6, 64.8, 61.7, 40.3, 33.7, 26.1, 18.5, 14.4, −5.1 ppm. HRMS (ESI) [M+H]+ calcd. for C12H25NO3Si 260.1676, found 260.1675.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:26][C:27]1([CH3:39])[CH2:31][C:30]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:29]=2[O:28]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([C:33]2[CH:34]=[CH:35][C:29]3[O:28][C:27]([CH3:26])([CH3:39])[CH2:31][C:30]=3[CH:32]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1nn(-c2ccc3c(c2)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 72 h
Yield: 97.2 %

Procedure:
A mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (1.2 g), copper(II) acetate (1.1 g), pyridine (1.2 mL), triethylamine (2.1 mL), molecular sieves 4 A (2.0 g) and dichloromethane (10 mL) was stirred for 3 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.4 g, 100%) as a pale-yellow liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.FC(F)(F)S(O[C:25]1[C:30]2[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:29]=2[O:28][C:27]([CH2:40][F:41])([CH2:38][F:39])[N:26]=1)(=O)=O.O>O1CCCC1.[Cl-].[Zn+2].[Cl-].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>[F:41][CH2:40][C:27]1([CH2:38][F:39])[N:26]=[C:25]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:30]2[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:29]=2[O:28]1
Reactant: Brc1ccccn1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(OS(=O)(=O)C(F)(F)F)=NC(CF)(CF)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccn1)=NC(CF)(CF)O2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 3 ml of anhydrous tetrahydrofuran solution of 0.21 ml of 2-bromopyridine was added dropwise 1.38 ml of 1.68M n-butyllithium hexane solution at -78° C. under nitrogen atmosphere. After 30 minutes, 4.26 ml of solution of 0.5M zinc chloride in dry tetrahydrofuran was added thereto and the mixture was stirred at -78° C. for 15 minutes and under ice-cooling for 15 minutes. To the mixture were added under ice-cooling 65 mg of tetrakis(triphenylphosphine)palladium (O) and 330 mg of 4-trifluoromethanesulfonyloxy-2,2-bisfluoromethyl-6-nitro-2H-1,3-benzoxazine. The mixture was warmed to room temperature and was stirred for additional 36 hours. Water was added to the reaction mixture which was then extracted with ethyl acetate and dried. The solvent was distilled off and the resultant residue was purified using column chromatography (developing solution, AcOEt:hexane=1:5) to obtain 110 mg of oily 2,2-bisfluoromethyl-6-nitro-4-(2-pyridyl)-2H-1,3-benzoxazine represented by the following formula.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[N:7](S(C2C=CC=CC=2)(=O)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2.[OH-].[K+].O>O1CCCC1.CO>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C1CCCO1)n2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2[nH]c(C3CCCO3)cc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a solution of the compound obtained in Example 13 (1) (210 mg) in a mixture of tetrahydrofuran/methanol (2:1, 15 ml), a 1N aqueous potassium hydroxide solution (1.6 ml) was added and the mixture was stirred at 100° C. for 2 hours. The reaction solution was then poured into water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane ethyl acetate=1:1) to obtain 113 mg of the desired product as a white powder.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>C(N(CC)CC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:28][CH2:27][C:23]1[O:22][CH:26]=[CH:25][CH:24]=1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: NCc1ccco1
Agent: Br
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3ccco3)c2)N1C

Procedure:
6.5 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 1.5 g of 2-furylmethyl amine and 3.5 g of triethyl amine and worked up. Melting point: 154° C. (decomposition).
Reaction SMILES: [CH:1](N1C(N)=CC(C2C=CN=CC=2)=N1)([CH3:3])[CH3:2].[NH2:16][C@@H:17]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[C:18]([NH:20][C:21]1[NH:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[CH:27]=2)[CH:22]=1)=[O:19]>>[NH2:16][C@@H:17]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=1)[C:18]([NH:20][C:21]1[N:25]([CH:1]([CH3:3])[CH3:2])[N:24]=[C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[CH:27]=2)[CH:22]=1)=[O:19]
Reactant: CNc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)[nH]n2)ccn1
Reactant: CC(C)n1nc(-c2ccncc2)cc1N
Product: CNc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)n(C(C)C)n2)ccn1
Yield: 75 %

Procedure:
This title compound was prepared starting from 29.A according the procedure described above for conversion of 18.0 to 18.E. The crude product was purified by flash chromatography on silica gel using 0-15% MeOH/CH2Cl2 for elution to provide 43.1 (510 mg, 75%). MS ESI (positive.) m/e: 397.1 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])[S:13][N:12]=1)[CH3:2].[NH:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:13][N:12]=[C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]4)[CH:7]=[CH:6][CH:5]=3)[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCc1c(C=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Reactant: O=C(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a solution of 5-[3-(2-ethyl-3-formylphenyl)-1,2,4-thiadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (D46) (110 mg) in dichloromethane (DCM) (5 mL) and methanol (5.00 mL) was added 3-azetidinecarboxylic acid (147 mg) and acetic acid (0.050 mL). The resulting solution was stirred at room temperature for overnight. Sodium triacetoxyborohydride (185 mg) was added and the reaction solution was stirred for 2 h. The solvent was removed in vacuo and the residue was purified by Mass Directed AutoPrep to give 1-{[3-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]methyl}-3 azetidinecarboxylic acid (E17) (37 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.03 (3H, t), 1.31 (6H, d), 2.93 (2H, q), 3.60 (1H, m), 4.22 (4H, m), 4.52 (2H, s), 4.89 (1H, m), 7.38 (1H, t), 7.42 (1H, d), 7.51 (1H, s br), 7.82 (1H, d), 8.27 (1H, dd), 8.42 (1H, d), 10.20 (1H, s br), 13.13 (1H, br s). δF (DMSO-d6, 376 MHz): −73.7. MS (ES): C26H26N4O3S requires 462. found 463.2 (M+H+).
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[F:22][C:23]1[CH:45]=[CH:44][C:26]([C:27]([C:29]2[C:38](O)=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:34]3)=[O:28])=[CH:25][CH:24]=1.S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[C:38]([O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([S:40]([NH2:43])(=[O:41])=[O:42])=[CH:34]3)=[O:28])=[CH:44][CH:45]=1
Reactant: NS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(O)ccc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
Pyridine (4.25 ml, 52.1 mmol) and trifluoromethanesulfonic anhydride (4.4 ml, 26.1 mmol) were added to a solution of 5-(4-fluorobenzoyl)-6-hydroxy-2-naphthalenesulfonamide (3.0 g, 8.7 mmol), [prepared as described in step 1 above], in methylene chloride (50 ml) at 0° C. After 0.5 h, 1N sodium bisulfate was added and the stirring was continued for an additional 30 minutes. The organic layer was separated, washed with brine, and dried over sodium sulfate. The solvent was removed in vacuo to give 3.1 g of 5-(4-fluorobenzoyl)-6-trifluoromethylsulfonyloxy-2-naphthalenesulfonamide as an oil (75% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].CN(C=O)C.S(Cl)(Cl)=O.[Si:24]([O:31][CH2:32][CH2:33][CH2:34][NH2:35])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(Cl)Cl.CCN(CC)CC>[Si:24]([O:31][CH2:32][CH2:33][CH2:34][NH:35][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])([C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:26])[CH3:25]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Reactant: CC(C)(C)[Si](C)(C)OCCCN
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a stirred solution of 3-nitro-quinolin-4-ol (5 g) in DCM (70 mL) was added DMF (2.3 mL) then thionyl chloride (2.1 mL) and the reaction mixture was refluxed for 3 h. The solution was cooled to 0° C. and 3-{[tert-butyl(dimethyl)silyl]oxy}propan-1-amine (6 g) was added followed by dropwise addition of Et3N (12 mL). The reaction mixture was stirred at rt for 2 h, then partitioned between DCM and saturated NaHCO3 solution. The organic layer was washed with water, dried, and the solvent evaporated under reduced pressure. The residue was triturated with iso-hexane to leave the subtitle compound (8.7 g).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:15]=[N:16][C:17]([C:18]([O-])=[O:19])=[C:13]3[CH2:12][N:11]([CH3:21])[C:10](=[O:22])[C:9]=2[CH:23]=1>C(O)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:15]=[N:16][C:17]([C:18]([NH:2][NH2:3])=[O:19])=[C:13]3[CH2:12][N:11]([CH3:21])[C:10](=[O:22])[C:9]=2[CH:23]=1
Reactant: CN1Cc2c(C(=O)[O-])ncn2-c2ccc(F)cc2C1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)NN)ncn2-c2ccc(F)cc2C1=O
Yield: 96 %

Procedure:
13 ml of hydrazine hydrate were added to a suspension of 7.0 g (23 mmol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylate in 70 ml of ethanol and the mixture was heated at reflux for 3 hours. After cooling to 0° the crystals obtained were filtered off and there were obtained 6.43 g (96%) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide as colourless needles of m.p. 288°-290°.