Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([S:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=1)[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.Cl>CO>[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([S:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=1)[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccccc2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(SC(Cn2ccnc2)c2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
694 μl of a 1N aqueous solution of sodium hydroxide were added to a solution of 61.5 mg of methyl 4-[1-(2-hydroxyphenyl)-2-(imidazol-1-yl)ethylthio]benzoate (prepared as described in Example 33) in 694 μl of methanol, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then neutralized with 694 μl of a 1N aqueous solution of hydrochloric acid, and methanol was removed by distillation under reduced pressure. The remaining solution was subjected to chromatography through a Lobar column (Lichroprep, trade mark, RP-8, size B, produced by Merck) to give 32.2 mg of the title compound as a powdery substance, melting at 186°-190° C., from the fraction eluted with 30% v/v aqueous methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[OH-].[Na+].[Br:12][CH2:13][CH2:14]Br>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH2:14][CH2:13][Br:12]
Reactant: Oc1cc(Cl)ccc1Br
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(Br)c(OCCBr)c1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
To a suspension of 2-bromo-5-chloro-phenol (2.58 g, 12.44 mmol) in water (8 mL) was added sodium hydroxide (995 mg, 24.88 mmol) and the solution heated to reflux for 1 h and then allowed to cool to room temperature. 1,2-dibromoethane (4.67 g, 24.88 mmol) was added and the mixture heated at reflux for 25 h. The solution was allowed to cool to room temperature and partitioned between EtAOc and water. The aqueous was washed with saturated sodium hydrogen carbonate, water and brine and then dried (MgSO4) and concentrated. Material was purified using an ISCO (0-5% EtOAc/hexanes) to afford 1-bromo-2-(2-bromoethoxy)-4-chlorobenzene as a white solid (1.30 g, 33%). 1H NMR (500 MHz, d6-DMSO) δ 7.62 (1H, d), 7.26 (1H, s), 7.02 (1H, d), 4.46 (2H, t), 3.83 (2H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.[Cl:16][C:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>O1CCCC1>[Cl:16][C:17]1([C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]4[CH:11]([C:12](=[O:15])[NH:13][N:14]=3)[CH2:10]4)=[CH:6][CH:7]=2)=[O:21])[CH2:19][CH2:18]1
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Reactant: O=C(Cl)C1(Cl)CC1
Solvent: C1CCOC1
Product: O=C1NN=C(c2ccc(NC(=O)C3(Cl)CC3)cc2)C2CC12
Yield: 62.4 %

Procedure:
5.0 g (24.8 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one, 4.5 g (32.4 millimoles) of 1-chlorocyclopropanecarboxylic acid chloride and 100 ml of absolute tetrahydrofuran are kept at room temperature for 6 hours. The product is filtered off at 10° C., washed first with tetrahydrofuran and then with water, and recrystallized from methanol. 4.7 g (62% of theory) of 2-[p-(1-chlorocyclopropylcarbonylamino)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are isolated as colorless crystals, of melting point 221°-222° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=O)[CH:16]=[CH:17][CH:18]=1.[H][H]>C(OCC)(=O)C.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(C=Cc1cccc(OCc2ccc3ccccc3n2)c1)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1ccc(CCCc2cccc(OCc3ccc4ccccc4n3)c2)cc1

Procedure:
A solution of 4-(3-(3-(2-quinolinylmethyloxy)phenyl)-1-oxo-2-propen-1-yl)phenol (0.008 mol) in ethyl acetate (150 ml) is shaken under 50 psi of hydrogen gas in the presence of 10% palladium on carbon catalyst (1.0 g). The reaction mixture is filtered through a celite pad and evaporated to give 4-(3(3-(2-quinolinylmethyloxy)phenyl)propyl)phenol.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]([O:27][C:28](=[O:33])[CH:29](Br)[CH2:30]Br)[CH3:26]>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:30][CH:29]2[C:28]([O:27][CH2:25][CH3:26])=[O:33])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: c1ccc(CNCCNc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1c1ccccc1
Temperature: 40 °C
Yield: 29.2 %

Procedure:
A mixture of this ethylenediamine (31 g, 0.137 mole) and triethylamine (28 g, 0.277 mole) was added dropwise over 30 minutes to a stirred solution of ethyl-2,3-dibromopropionate (35.0 g, 0.135 mole) dissolved in 200 mL of toluene and heated to 40° C. After the addition was complete, the reaction was heated at 80°-85° C. for 7 hours, cooled to room temperature, and partitioned between water and toluene. The organic layer was separated, dried, and stripped of all solvent under reduced pressure to yield 38 g of the crude product. Chromatographic purification gave 12.8 g of ethyl 1-phenyl-4-(phenylmethyl)-2-piperazinecarboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)[N:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Clc1cncc(Cl)n1
Solvent: C1COCCO1
Product: Fc1ccc(-c2cncc(Cl)n2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
A mixture of 2,6-dichloropyrazine (2.75 g, 18.3 mmol), 4-fluorophenyl boronic acid (2.3 g, 16.5 mmol) and palladium tetrakis triphenylphosphine (0.1 g) in dioxane (50 mL) was stirred at 60° C. for one hour. The mixture was cooled and partitioned between water and diethyl ether. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether and methanol to give 1.2 g of 2-chloro-6-(4-fluoro-phenyl)-pyrazine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][O:14][CH2:15]Cl)=[CH:11][CH:10]=1.[Cl:19][C:20]1[CH:21]=[N:22][C:23](=[O:26])[NH:24][CH:25]=1.C(N(CC)CC)C>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][O:14][CH2:15][N:24]2[CH:25]=[C:20]([Cl:19])[CH:21]=[N:22][C:23]2=[O:26])=[CH:11][CH:10]=1
Reactant: ClCOCc1ccc(COC2CCCCO2)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(Cl)cn1COCc1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Chloromethyl 4-(tetrahydropyran-2-yloxymethyl)benzyl ether (see Preparation 12) (4.7 mmol) in dichloromethane (40 ml) was added dropwise with stirring to a solution of 5-chloropyrimidin-2-one (4.7 mmol) and triethylamine (4.7 mmol) in dichloromethane (10 ml). The mixture was stirred at room temperature for 2 hours and was then washed with water, the organic solution dried (MgSO4) and the solvent distilled off to yield a crude product in 89% yield (1.53 g), which was extracted with ether and the residual material purified on neutral alumina eluting with dichloromethane and subsequently with 10% MeOH in dichloromethane; yield 0.42 g (26%) of the non-crystalline title compound. 1H NMR (CDCl3): δ1.4-2.0 (6H, m, THP), 3.3-4.3 (2H, m), 4.5-4.9 (2CH2, CH), 5.37 (NCH2), 7.38 (Ph), 7.88 and 8.53 (H-4, H-6, J 4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COCN(c1cc(C)cnc1C(=O)c1c(C)ccnc1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(C(=O)c2c(C)ccnc2C)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 32.9 %

Procedure:
A mixture of 4-chloro-N-[2-(2,4-dimethyl-pyridine-3-carbonyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (260 mg, 0.49 mmol) in 4M HCl in dioxane (5 mL) and water (1 mL) was refluxed for 3 h. Reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified by flash chromatography (SiO2, 70% EtOAc-hexanes) to afford 4-chloro-N-[2-(2,4-dimethyl-pyridine-3-carbonyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (78 mg) as an off white solid (after lyophilization) in 33% yield. ESMS m/z (relative intensity): 484 (M+H)+ (100).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[O:15][C:16]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:17][N:18]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C>Br.C(O)(=O)C>[N+:11]([C:7]1[CH:6]=[C:5]([C:14]2[O:15][C:16]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:17][N:18]=2)[CH:4]=[C:3]([OH:2])[C:8]=1[OH:9])([O-:13])=[O:12]
Reactant: COc1cc(-c2nnc(-c3cccnc3C(F)(F)F)o2)cc([N+](=O)[O-])c1OC
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(-c2nnc(-c3cccnc3C(F)(F)F)o2)cc(O)c1O
Temperature: 140 °C

Procedure:
A suspension of 2-(3,4-dimethoxy-5-nitrophenyl)-5-(2-(trifluoromethyl)pyridin-3-yl)-1,3,4-oxadiazole (0.289 g, 0.73 mmol) in a mixture of 48% hydrobromic acid (5 mL) and 30% hydrogen bromide in acetic acid (5 mL) was heated at 140° C. overnight and then allowed to cool to room temperature. After evaporation to dryness under reduced pressure, toluene (10 mL) was added to the residue and re-evaporated under reduced pressure. The resulting solid was recrystallised from isopropanol to give 3-nitro-5-[5-(2-trifluoromethyl-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diol as a yellow solid, 0.183 g, (68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].Br[CH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>C(COC)OC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: N#Cc1cccc(CBr)c1
Agent: [Na+]
Solvent: COCCOC
Product: N#Cc1cccc(CS(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
A dimethoxyethane (15 ml) suspension of sodium 4-chlorobenzenesulfinate (270 mg, 1.36 mmol) and 3-bromomethylbenzonitrile (222 mg, 1.13 mmol) was stirred at 70° C. for 3 days. After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed successively with water and brine and then, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column and the fraction obtained from the hexane:ethyl acetate (=3:1) eluate was concentrated under reduced pressure, whereby the title compound (318 mg, 96%) was obtained as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1>>[Cl:24][C:23]1[C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: Nc1ncccc1Cl
Product: Cc1onc(-c2ccccc2)c1-c1cn2cccc(Cl)c2n1
Yield: 76 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-3-chloropyridine instead of 2-aminopyridine, to the title compound (117 mg, 76%) which was obtained as a yellow foam. MS: m/e=310.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:9]=[C:8]([CH2:10]OS(C)(=O)=O)[C:7]=2[CH:16]=1.[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1)=[O:21])[CH3:18].C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:10][C:8]2[C:7]3[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:9]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: COc1ccc2c(c1)C(COS(C)(=O)=O)=C2
Reactant: CCOC(=O)C1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCN(CC2=Cc3ccc(OC)cc32)C1
Reaction time: 18 h

Procedure:
To a solution of 7.27 g (30 mmol) of methanesulphonic acid (5-methoxybenzocyclobuten-1-yl)methyl ester in 60 ml of dimethylformamide there are added first 5.66 g (36 mmol) of piperidine-3-carboxylic acid ethyl ester and then 9.70 g (75 mmol) of N-ethyl-N,N-diisopropylamine. The mixture is stirred at 60° for 18 hours and, after cooling,is concentrated by evaporation under a high vacuum. The residue is taken up in diethyl ether and washed with water, and the organic phase is extracted with 2N hydrochloric acid. The hydrochloric acid extracts are combined, rendered alkaline at reduced temperature with concentrated sodium hydroxide solution and extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated to dryness by evaporation under reduced pressure. 1-[(5-methoxybenzocyclobuten-1-yl)methyl]-piperidine-3-carboxylic acid ethyl ester is obtained in the form of a yellow oil.
Reaction SMILES: [O:1]1[CH2:4][CH:3](/[CH:5]=[N:6]/[S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH2:2]1.[CH3:13][Mg]Br>ClCCl>[O:1]1[CH2:4][CH:3]([C@H:5]([NH:6][S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH3:13])[CH2:2]1
Reactant: CC(C)(C)[S@](=O)/N=C/C1COC1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@@H](N[S@@](=O)C(C)(C)C)C1COC1
Temperature: -76 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
In a round-bottomed flask, (S)-2-methyl-propane-2-sulfinic acid 1-oxetan-3-yl-meth-(E)-ylideneamide (172 mg, 0.91 mmol) was dissolved in dichloromethane (3.6 ml). The colorless solution was cooled to −76° C. and methylmagnesium bromide (3.0 M in diethyl ether, 0.91 ml, 2.73 mmol) was added dropwise. The reaction mixture was stirred at −76° C. for 3 h and then allowed to warm slowly to room temperature overnight. The reaction was quenched with saturated NH4Cl-solution then extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to provide 143 mg (77%) of (S)-2-methyl-propane-2-sulfinic acid ((R)-1-oxetan-3-yl-ethyl)-amide as a light yellow oil which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.O[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=2)[CH:22]=1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Reactant: Oc1cccnc1
Product: CN(C(=O)Oc1ccc(COc2cccnc2)cc1)c1ccccc1
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 3-hydroxypyridine. 1H NMR (400 MHz; CDCl3): δ 3.44 (br s, 3H), 5.12 (s, 2H), 7.17 (br s, 2H), 7.27-7.46 (m, 9H), 8.29 (br s, 1H), 8.49 (br s, 1H); HPLC-MS: m/z=335.0 (M+1); Rt=2.74 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH:10]([CH2:14]Br)[CH2:11][C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:14][CH:10]1[CH2:11][C:12]#[N:13]
Reactant: N#CCC(Br)CBr
Reactant: Oc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCC1CSc2ccccc2O1
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows: To the stirred, refluxing solution of 21 g of 2-hydroxy-thiophenol in 290 ml of acetone is added dropwise 12.5 g of 3,4-dibromo-butyronitrile along with small portions of 15.8 g of anhydrous potassium carbonate. After 30 minutes, the double addition procedure with said amounts of dibromo compound and potassium carbonate is repeated, and after a further 30 minutes said procedure is repeated a third time. The mixture is then refluxed for 20 hours, cooled, filtered, the residual salts washed with acetone, and the filtrate evaporated. The residue is distilled (bulb to bulb), and the fraction boiling at 185°/0.5 mm Hg collected, to yield the 2-(1,4-benzoxathian-2-yl)-acetonitrile.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([N:18]([OH:32])[C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[NH2:5][CH2:9][CH:10]([N:18]([OH:32])[C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cn1nccc1-c1csc(C(=O)N(O)C(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1-c1csc(C(=O)N(O)C(CN)Cc2ccccc2)c1
Reaction time: 1 h
Yield: 64.8 %

Procedure:
1,1-Dimethylethyl[2-(hydroxy{[4-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (84 mg, 0.19 mmol) was dissolved in DCM (2 mL) and treated with TFA (1 mL). The reaction was stirred over 1 h, and concentrated, and purified by reverse-phase HPLC (C18 column: H2O/CH3CN, 40-10%), and concentrated to afford the bis-TFA salt of the title compound (51.2 mg, 64.8%). LC-MS (ES) m/z 357 (M+H)+, 1H NMR (d4-MeOD, 400 MHz) δ ppm 8.03 (s, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 6.46 (d, J=1.8 Hz, 1H), 7.34-7.18 (m, 5H), 5.16 (m, 1H), 3.95 (s, 3H), 3.38 (dd, J=13.1, 10.6 Hz, 1H), 3.17-3.11 (m, 2H), and 2.95 (dd, J=13.6, 6.6 Hz, 1H)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([Cl:24])[CH:18]=[C:17]2[Cl:25].Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([Cl:24])[C:18]([CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)=[C:17]2[Cl:25]
Reactant: Clc1cc(Cl)c2cc(Br)ccc2n1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (1.40 mL, 9.96 mmol) in THF (12 mL) cooled to 0° C. was added n-butyllithium (2.5 M solution in hexanes, 3.80 mL, 9.50 mmol) dropwise via syringe. The reaction mixture was stirred at 0° C. for 10 minutes then cooled to −78° C. at which time a separate solution of 6-bromo-2,4-dichloroquinoline (1.80 g, 6.51 mmol, Intermediate 44: step b) in THF (29 mL) was added dropwise via syringe. The mixture was stirred at −78° C. for 30 minutes followed by the addition of 4-(bromomethyl)benzonitrile (1.52 g, 7.74 mmol) in THF (5 mL). After an additional 10 minutes of stirring at −78° C., the reaction was transferred to an ice bath and warmed to ambient temperature over 5 hours. The reaction was quenched with water and the aqueous phase was extracted with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% EtOAc-Hexanes) to provide the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([CH2:22][OH:23])=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[C:19]([CH:22]=[O:23])=[N:20][N:21]=[C:10]3[CH2:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: O=Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A mixture of 1.3 g of 6-phenyl-8-chloro-4H-s-triazolo [4,3-a][1,4]benzodiazepine-1-methanol [cp., e.g. German `Offenlegungsschrift` No. 2,156,472, Belgian Pat. No. 775,558] , 3.4 g of manganese dioxide and 80 ml of benzene is refluxed for 2 hours. The reaction mixture is then filtered through a layer of silica gel, and the filtrate concentrated by evaporation. The residue is chromatographed through silica gel (Merck, 0.063 - 0.2 mm particle size) with various ethyl acetate/ethanol mixtures of increasing ethanol content as the eluant. The fractions eluted with ethyl acetate/ethanol (4:1) are combined and concentrated by evaporation. The residue is crystallised from ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo[4,3-a] [1,4]benzodiazepine-1-carboxaldehyde, M.P. 161°-163°.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([OH:10])[CH2:6]2.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21]>>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([O:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21])[CH2:6]2
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CN1C2CCC1CC(O)C2
Product: Cc1cc([N+](=O)[O-])ccc1OC1CC2CCC(C1)N2C

Procedure:
8-Methyl-8-aza-bicyclo[3.2.1]octan-3-ol was reacted with 1-Fluoro-2-methyl-4-nitrobenzene according to method D. The product with the molecular weight of 276.34 (C15H20N2O3) was obtained in this way; MS (ESI) 277 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:20])OC2C=CC([N+]([O-])=O)=CC=2)=[CH:3][CH:2]=1.Cl.[NH2:22][C:23]1[C:24]2[C:34]([O:35][CH2:36][C@H:37]3[CH2:42][CH2:41][CH2:40][NH2+:39][CH2:38]3)=[CH:33][CH:32]=[CH:31][C:25]=2[NH:26][S:27](=[O:30])(=[O:29])[N:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:22][C:23]1[C:24]2[C:34]([O:35][CH2:36][C@H:37]3[CH2:42][CH2:41][CH2:40][N:39]([C:9]([NH:8][CH2:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:20])[CH2:38]3)=[CH:33][CH:32]=[CH:31][C:25]=2[NH:26][S:27](=[O:29])(=[O:30])[N:28]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCC[NH2+]C3)c21
Reactant: O=C(NCc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)NCc4ccncc4)C3)c21

Procedure:
A solution of 4-nitrophenyl (pyridin-4-ylmethyl)carbamate (Example 27d, 27.3 mg, 100 umol), (S)-3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 2a, 34.6 mg, 0.10 mmol) and K2CO3 in DMF (1 mL) was stirred at room temperature overnight. The resulting mixture was filtered and purified by preparative HPLC (10-90% acetonitrile in water) to provide the title product as a white solid. MS=445 (MH+).