Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10][CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)(Cl)(=O)=[O:13].CCO>C(Cl)Cl>[CH3:11][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:13]
Reactant: CSc1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: CS(=O)c1cccc([N+](=O)[O-])c1
Temperature: -20 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
A solution of 3-nitro thioanisol (96 g, 568 mmol) in DCM (100 mL) is added dropwise to a cooled solution of sulfuryl chloride (96 g, 711 mmol) in DCM (600 mL) at −60° C. The mixture is stirred for 4 h at −20° C., then cooled to −60° C., and 350 mL of EtOH are carefully added. The reaction is then allowed to warm up to rt, subsequently, most of the solvent is evaporated, the residue is poured in sat. aq. NaHCO3, and the solid product is filtered off and carefully washed with hexane on the filter, then air-dried to give the desired sulfoxide (95 g, 90% yield).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH3:38])=[C:32]([O:39][CH2:40][CH3:41])[CH:31]=1>CC(N(C)C)=O>[CH2:40]([O:39][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[O:36][CH2:37][CH3:38])[CH2:29][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)[CH3:41]
Reactant: CCOc1ccc(CCl)cc1OCC
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCOc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1OCC
Temperature: 60 °C
Yield: 71.2 %

Procedure:
tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.150 g, 0.522 mmol), cesium carbonate (0.255 g, 0.783 mmol) and 4-(chloromethyl)-1,2-diethoxybenzene (0.168 g, 0.783 mmol) were taken up in DMA (2 mL) and heated to 60° C. for 16 h in a 20 mL sealed scintillation vial. The mixture was cooled down to room temperature and filtered by vacuum filtration through a glass fiber paper. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (173.1 mg).
Reaction SMILES: C1([Li])C=CC=CC=1.[N:8]([CH:11]([CH3:32])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]2[CH2:18][C:19]3[C:24]([C:14]1=2)=[CH:23][C:22](C(OS(C)(=O)=O)=O)=[CH:21][CH:20]=3)=[N+:9]=[N-:10].C([O:35]CC)C.[Cl-].[NH4+]>O.O1CCCC1>[N:8]([CH:11]([CH3:32])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]2[CH2:18][C:19]3[C:24]([C:14]1=2)=[CH:23][C:22]([OH:35])=[CH:21][CH:20]=3)=[N+:9]=[N-:10]
Reactant: CCOCC
Reactant: CC(Cn1ccc2c1-c1cc(C(=O)OS(C)(=O)=O)ccc1C2)N=[N+]=[N-]
Agent: [Cl-]
Agent: [Li]c1ccccc1
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cn1ccc2c1-c1cc(O)ccc1C2)N=[N+]=[N-]
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A 2M phenyllithium solution was added dropwise over 5 minutes to a solution, cooled to 0°, of 3.55 g of (RS)-1-(2-azido-propyl)-7-mesyloxycarbonyl-1,4-dihydro-indeno[1,2-b]pyrrole, 90 ml of anhydrous diethyl ether and 90 ml of anhydrous tetrahydrofuran. After 15 minutes at this temperature, an additional 5.87 ml of the phenyllithium solution were added dropwise and the mixture was stirred for an additional 5 minutes. Subsequently, the reaction mixture was treated with 50 ml of a saturated ammonium chloride solution and 25 ml of water. The mixture was extracted once with 50 ml of ethyl acetate and the aqueous phase was made slightly acidic with 1N hydrochloric acid and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated in a vacuum. 2.7 g (99%) of (RS)-1-(2-azido-propyl)-7-hydroxy-1,4-dihydro-indeno[1,2-b]pyrrole were obtained as a brown oil.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)(=[O:38])=[O:37])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc(OC)cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 4-methoxybenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (24%); 1H NMR (d6-DMSO) δ 12.04 (br s, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.38-7.07 (m, 15H), 6.84 (d, J=8.0 Hz, 2H), 6.39 (d, J=15.7 Hz, 1H), 3.80 (s, 3H), 2.35 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 525 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[Cl-].[OH:11][NH3+:12].C(N(CC)CC)C>>[OH:11][N:12]=[C:8]([C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[NH2:9]
Reactant: [NH3+]O
Reactant: Cc1ccc(C#N)cn1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: Cc1ccc(C(N)=NO)cn1

Procedure:
1.0 g (8.5 mmol) of 6-methylpyridine-3-carbonitrile, 882 mg (12.7 mmol) of hydroxylammonium chloride and 1.4 ml (10.2 mmol) of triethylamine were reacted according to the General Method 5A. Yield: 1.11 g (87% of theory)
Reaction SMILES: C(OC([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)=O)(C)(C)C.O1CC(=O)N=N1.C(OC(=O)CCNC(=O)C1C=CC(C2[NH:38][O:39][C:40](=[O:42])N=2)=CC=1)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:39]1[C:40](=[O:42])[N:14]=[C:13]([C:12]2[CH:11]=[CH:10][C:9]([NH2:8])=[CH:16][CH:15]=2)[NH:38]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2nc(=O)o[nH]2)cc1
Agent: O=C1CON=N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2nc(=O)o[nH]2)cc1

Procedure:
Compound 14 (3.25 g, 14.9 mmol) was converted into oxadiazolone 15 as described earlier for the preparation of compound 3. The resulting crude light orange solid was stirred for 5 h in a mixture of DCM (15 mL) and TFA (8 mL). Concentration under reduced pressure and evaporation with toluene (2×10 mL) gave a brown solid which was purified by silica gel (40 g) column chromatography (eluent: EtOAc) to yield compound 16 (1.81 g, 69% over the three steps). Rf 0.5 (EtOAc).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:21]3=[C:22]4[C:16](=[C:17]5[N:26]([CH3:27])[CH:25]=[CH:24][C:23]([NH2:28])=[C:18]5[CH:19]=[CH:20]3)[C:15](=[O:29])[NH:14][C:13]4=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:30][C:31]1[S:32][C:33]([CH2:36][C:37](O)=[O:38])=[CH:34][N:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:21]3=[C:22]4[C:16](=[C:17]5[N:26]([CH3:27])[CH:25]=[CH:24][C:23]([NH:28][C:37](=[O:38])[CH2:36][C:33]6[S:32][C:31]([CH3:30])=[N:35][CH:34]=6)=[C:18]5[CH:19]=[CH:20]3)[C:15](=[O:29])[NH:14][C:13]4=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N2CC=c3[nH]c(=O)c4c5c(ccc2c3-4)=C(N)C=CN5C)CC1
Reactant: Cc1ncc(CC(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCC(N2CC=c3[nH]c(=O)c4c5c(ccc2c3-4)=C(NC(=O)Cc2cnc(C)s2)C=CN5C)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 95.3 %

Procedure:
A mixture of Example 73d (0.02 g, 0.051 mmol), 2-(2-methylthiazol-5-yl)acetic acid (0.012 g, 0.077 mmol), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.029 g, 0.077 mmol) in N,N-dimethyl acetamide (0.5 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (0.027 mL, 0.153 mmol) and stirred at ambient temperature for 22 hours. The reaction mixture was partitioned between ethyl acetate and water and washed with saturated aqueous sodium chloride. The aqueous layers were combined, saturated with solid sodium chloride and extracted with ethyl acetate (4×100 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-15% methanol in dichloromethane). The material was further purified by reverse phase HPLC(C18, acetonitrile/water (0.1% TFA), 10-100%) to provide 0.0258 g (78%) of the title compound as the TFA salt. 1H NMR (400 MHz, PYRIDINE-d5) δ 11.24 (s, 1H), 10.34 (s, 1H), 8.34 (d, J=2.44 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J=2.75 Hz, 1H), 7.35 (s, 1H), 7.21 (d, J=8.54 Hz, 1H), 6.89 (s, 1H), 4.20 (s, 2H), 4.13 (s, 3H), 4.07 (s, 2H), 3.64 (m, 1H), 3.25 (m, 1H), 2.63 (m, 2H), 2.55 (s, 3H), 2.59 (m, 1H), 1.93 (s, 3H), 1.69 (m, 2H), 1.50 (m, 2H). MS (ESI+) m/z 531.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([S:13][CH3:14])[N:5]=[C:4]([CH3:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1.O>CN(C=O)C.[Cu](I)I>[CH3:15][C:4]1[N:5]=[C:6]([S:13][CH3:14])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=2)[N:3]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1SC
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1c(Oc2cccc(C(F)(F)F)c2)nc(C)nc1SC

Procedure:
A solution of methyl 2-(4-chloro-2-methyl-6-methylthio-pyrimidin-5-yl)-acetate (4.9 g) in DMF is added to a suspension of anhydrous potassium carbonate 5.6 g), copper iodide (1.0 g) and 3-trifluoromethylphenol (3.3 g) in DMF (50 ml) at room temperature. The mixture is heated to +120° C. for 90 minutes and then cooled. The cooled mixture is poured into water and extracted successively with ethyl acetate (2×50 ml) and then the organic phase is dried over anhydrous sodium sulfate. Evaporation and drying under high vacuum gives the methyl 2-[2-methyl-4-methylthio-6-(3-trifluoromethyl-phenoxy)-pyrimidin-5-yl]-acetate in form of a dark oil. NMR (CDCl3): 7.25-7.55 (m, 4H); 3.78 (s, 3H); 3.70 (s, 3H); 2.62 (s, 3H); 2.46 (s, 3H).
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].Cl.C([O-])(O)=O.[Na+].[CH3:16][O:17][C:18]([C:20]1[S:24][C:23]([NH2:25])=[N:22][C:21]=1[CH3:26])=[O:19]>O.O1CCOCC1>[CH3:16][O:17][C:18]([C:20]1[S:24][C:23]2=[N:25][CH:1]=[CH:2][N:22]2[C:21]=1[CH3:26])=[O:19]
Reactant: CCOC(CBr)OCC
Reactant: COC(=O)c1sc(N)nc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1sc2nccn2c1C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of bromoacetaldehyde diethyl acetal (29.3 mmol, 1.26 eq) in water (200 mL) is treated dropwise with conc. hydrochloric acid (3.0 mL), stirred for 14 h at RT and heated for additional 30 min at 80° C. After cooling to RT NaHCO3 (37.9 mmol) is added carefully and the mixture is stirred for 2 h and treated with 2-Amino-4-methyl-thiazole-5-carboxylic acid methyl ester (23.2 mmol, 1.00 eq). After 1 h dioxane (130 mL) is added and the mixture is stirred at RT for 30 min and at 100° C. for 48 h. The organic solvents are removed in vacuo and the mixture is extracted several times with DCM and chloroform. The combined organic layers are dried over Na2SO4 and concentrated in vacuo to give the desired ester which is used without further purification. LC-MS: tR=0.55 min; [M+H]+=197.0.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:4][C@H:3]1[NH:5]C(=O)OCC1C=CC=CC=1.C(N(CC)CC)C.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl.[Pd]>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:5][C@@H:3]2[CH2:4][C@H:2]2[CH3:1])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C[C@@H]1C[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1C[C@H]1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of benzyl ((1R,2R)-2-methylcyclopropyl)carbamate (1.68 g, 8.2 mmol) in DCM (55 mL) was charged with 10 wt % Pd/C, then degassed and charged with hydrogen (50 PSI). The reaction was complete after 30 min and so was filtered over celite, rinsing with DCM (15 mL). The liquor was cooled to 0° C., and treated with triethylamine (3.43 mL, 24.6 mmol) and 4-bromobenzene-1-sulfonyl chloride (2.20 g, 8.61 mmol). The cold bath was removed and the reaction was stirred for 1 h. At completion, the reaction was washed with 0.5 M aq. HCl (2×20 mL) and brine (20 mL), dried over MgSO4 and concentrated to provide 4-bromo-N-((1R,2R)-2-methylcyclopropyl)benzenesulfonamide (2.06 g, 87% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.74-7.80 (m, 1H), 7.66-7.72 (m, 1H), 4.90 (br. s., 1H), 1.94 (dt, J=3.5, 1.8 Hz, 1H), 1.41 (t, J=7.3 Hz, 1H), 0.89-1.01 (m, 3H), 0.70-0.81 (m, 1H), 0.35-0.45 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C:9]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)(=[O:11])[CH3:10]>CN(C)C=O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:9](=[O:11])[CH:10]=[CH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccco1
Reactant: O=Cc1ccncc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccncc1)c1ccco1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 0.3 %

Procedure:
Dissolve anhydrous cobalt(II) acetate (700 mg, 4 mmol ) in dimethylformamide (150 mL). Add 2,2'-dipyridyl (600 mg, 4 mmol) and stir for 30 minutes. Add 4-pyridinecarboxaldehyde (5 g, 50 mmol) and 2-acetylfuran (5.5 g, 50 mmol). Heat at 80° C. for 18 hours. Evaporate the solvent and purify the residue by silica gel chromatography (1:1 toluene/ethyl acetate) to yield 30 mg of the title compound; mp 122°-124° C.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OO)(C)(C)C.[OH:13][N:14]1[C:19]([CH3:21])([CH3:20])[CH2:18][C:17](=[O:22])[CH2:16][C:15]1([CH3:24])[CH3:23]>[Mo](=O)(=O)=O.O>[CH:1]1([O:13][N:14]2[C:19]([CH3:20])([CH3:21])[CH2:18][C:17](=[O:22])[CH2:16][C:15]2([CH3:24])[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Reactant: C1CCCCC1
Agent: O=[Mo](=O)=O
Agent: CC(C)(C)OO
Solvent: O
Product: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Reaction time: 5 h
Yield: 98.7 %

Procedure:
A mixture of cyclohexane (215 ml, 2.0 moles), t-butyl hydroperoxide, 70% aqueous (77.1 g, 0.6 moles), molybdenum trioxide (1.44 g, 0.01 moles) and 1-oxyl-2,2,6,6-tetramethyl-4-piperidone (34 g, 0.2 moles) is charged into a 500 ml flask equipped with a Barrett trap. The mixture is stirred at reflux (80° C.) for two hours until no more water is collected. Then, the mixture is filtered by gravity into a pressure bottle and molybdenum trioxide (1.44 g, 0.01 mole) is added. Subsequently, the mixture is heated under stirring to 105° C. (2.34 bar) and held for 5 hours, until the color changes from deep orange to pale yellow. The mixture is filtered and the clear solution is washed with 10% aqueous sodium sulfite (100 ml) and subsequently with water (2×50 ml). The obtained clear solution is dried over sodium sulfate and then concentrated to give 50 g of the desired material as a clear yellow oil (Mass spectrum: m/e=253)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:7]2[C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=3[CH:14]=[CH:15][CH:16]=2)[CH2:2]1.[OH:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[CH:12]1[C:13]2[C:8](=[C:7]([NH:6][CH:3]3[CH2:4][CH2:5][N:1]([CH2:24][C:23]4[CH:22]=[C:21]([CH:28]=[CH:27][CH:26]=4)[O:20][CH2:19][CH2:18][OH:17])[CH2:2]3)[CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][N:11]=1
Reactant: c1cc(NC2CCNC2)c2ccncc2c1
Reactant: O=Cc1cccc(OCCO)c1
Product: OCCOc1cccc(CN2CCC(Nc3cccc4cnccc34)C2)c1

Procedure:
Reaction of N-(pyrrolidin-3-yl)isoquinolin-5-amine with 3-(2-hydroxyethoxy)benzaldehyde using the method of Example 8 afforded the title compound.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:11][CH:12](O)[CH:13]=[CH2:14].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11]([CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10])[CH:12]=[CH:13][CH3:14]
Reactant: C=CC(C)O
Reactant: O=C1CCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1Cc2ccccc2C1=O
Yield: 48 %

Procedure:
A solution of 29.5 g of 1-indanone, 73.5 ml 3-buten-2-ol, 77.0 ml of 2,2-dimethoxypropane and 400 mg of p-toluenesulfonic acid in 400 ml of toluene was boiled under reflux for 24 hours. After cooling, the solution was washed with 100 ml of saturated sodium hydrogen carbonate solution. The aqueous washing was extracted with 150 ml of ethyl acetate and the organic phases were combined, dried with magnesium sulfate and evaporated in a vacuum. Purification on silica gel (hexane/diethyl ether 7:1) yielded 19.8 g (48%) of (RS)-2-(2-buten-1-yl)-1-indanone as a pale yellow oil.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:39]1[S:43][N:42]=[CH:41][N:40]=1)[S:7]([C:10]1[C:37]([F:38])=[CH:36][C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3/[CH:25]=[CH:26]/[CH2:27][NH:28]C(=O)OC(C)(C)C)[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][CH2:27]/[CH:26]=[CH:25]/[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:14]1[C:13]2[CH:36]=[C:37]([F:38])[C:10]([S:7]([NH:6][C:39]3[S:43][N:42]=[CH:41][N:40]=3)(=[O:9])=[O:8])=[CH:11][C:12]=2[O:16][C:15]1=[O:17]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n(Cc4ccccc4/C=C/CNC(=O)OC(C)(C)C)c3cc2F)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC/C=C/c1ccccc1Cn1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(F)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound of Formula 12-2 thus prepared (125 mg, 0.176 mmol) was placed into a 1 dram vial containing 702 μL of DCM and 176 μL of TFA at ambient temperature (RT). After 20 minutes of stirring at RT, LCMS indicated complete consumption of was placed 125 mg of 12-2. The reaction mixture was concentrated in vacuo, dissolved in MeOH (1 mL), filtered and purified by reverse-phase HPLC (5-60% MeCN in water with 0.1% TFA, C18 column) to give 12-3 (3-{2-[(1E)-3-Aminoprop-1-en-1-yl]benzyl}-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydro-1,3-benzoxazole-6-sulfonamide) as a white solid. 1H NMR δ (ppm)(DMSO-d6): 8.40 (1H, s), 7.95 (2H, br s), 7.77 (1H, d, J=5.32 Hz), 7.50 (1H, d, J=7.71 Hz), 7.35 (1H, t, J=7.54 Hz), 7.28 (1H, t, J=7.56 Hz), 7.21 (3H, t, J=7.71 Hz), 7.09 (2H, d, J=12 Hz), 6.16-6.09 (2H, m), 5.12 (2H, s). HRMS C19H17FN5O4S2 [M+H] calc 462.0701, obs 462.0706.
Reaction SMILES: [Br:1]Br.[CH2:3]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)[CH3:4]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:9]1[CH:10]=[CH:11][C:6]([S:5][CH2:3][CH3:4])=[CH:7][C:8]=1[F:12]
Reactant: CCSc1cccc(F)c1
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCSc1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
Bromine (0.3 ml) was added to a solution of 1-ethylsulfanyl-3-fluoro-benzene (1 g) in chloroform (20 ml) at 0° C. then warmed to RT. After 2 h the mixture was diluted with DCM, washed with aq. sodium thiosulphate solution, dried, and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% diethylether/iso-hexane. Yield 1.2 g
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:27])[C:24]=3[F:26])[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.NC1CCN(CCN2C3C(=CC=C(F)C=3)N=CC2=O)CC1>ClCCl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:27])[C:24]=3[F:26])[N:19]=[CH:18][C:17]2=[O:28])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)c(F)c32)CC1
Agent: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CCn2c(=O)cnc3ccc(F)c(F)c32)CC1

Procedure:
tert-Butyl{1-[2-(7,8-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 154, 320 mg, 0.78 mmol) was reacted with trifluoroacetic acid in dichloromethane as described for Intermediate 140 to give 240 mg (quantitative) of the crude product as an oil.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:30])[C:4]([C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:27]=1)=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:8][CH:7]=1.N1C(C)=CC(C)=CC=1C.Cl[C:41]([O:43][CH3:44])=[O:42].Cl>C1(C)C=CC=CC=1>[CH3:44][O:43][C:41](=[O:42])[N:30]=[C:3]([S:2][CH3:1])[C:4]([C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]2[O:26][CH2:25][O:24][CH2:23][C:22]=2[CH:27]=1)=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([CH3:17])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: COc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCOC2
Reactant: COC(=O)Cl
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: Cc1ccccc1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 23.8 g of the crude product of 2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]thioacetimidic acid methyl ester in 100 ml of toluene there were added 32 ml of collidine and 15 ml of methyl chloroformate, and the mixture was stirred at 80° C. for 1 hour under a nitrogen atmosphere. After cooling the reaction mixture, 1N hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (12.98 g) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][P:11]([O-:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:21]([C:24]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[C:28]([CH:35]([CH3:37])[CH3:36])[C:25]=1[CH2:26]Br)([CH3:23])[CH3:22].P([O-])([O-])[O-]>O1CCCC1>[CH2:13]([O:12][P:11]([CH2:26][C:25]1[C:24]([CH:21]([CH3:23])[CH3:22])=[CH:31][C:30]([CH:32]([CH3:34])[CH3:33])=[CH:29][C:28]=1[CH:35]([CH3:37])[CH3:36])(=[O:20])[O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)c1cc(C(C)C)c(CBr)c(C(C)C)c1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [O-]P([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)c1cc(C(C)C)c(CP(=O)(OCc2ccccc2)OCc2ccccc2)c(C(C)C)c1
Temperature: 25 °C

Procedure:
Sodium hydride (2.0 g, 50 mmol), was added in portions to dibenzylphosphite (13.0 g, 50 mmol) in tetrahydrofuran (250 mL) at room temperature. When no further reaction was apparent, added 2,4,6-triisopropylbenzyl bromide (14.47 g, 49 mmol) and stirred at room temperature. Stirred overnight at room temperature, added more phosphite anion (11.94 g phosphite, 1.30 g NaH), and stirred over 2 days at room temperature. The reaction mixture was concentrated, the residue was taken up in ethyl acetate, washed with 10% aqueous citric acid solution, brine, dried (magnesium sulfate), filtered, and concentrated to an oil. The oil was chromatographed on silica gel using 4:1 hexanes/ethyl acetate as eluant. The product was obtained as a solid in two portions, 17.47 g, (73%). Analysis calculated for (C30H39O3P).