Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:28]([F:29])=[CH:27][C:5]([O:6][C@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:8]2=[O:26])=[C:4]([F:30])[CH:3]=1.[CH3:31][S:32]([O-:34])=[O:33].[Na+].[C@H]1(N)CCCC[C@@H]1N>CS(C)=O.CCOC(C)=O>[F:30][C:4]1[CH:3]=[C:2]([S:32]([CH3:31])(=[O:34])=[O:33])[C:28]([F:29])=[CH:27][C:5]=1[O:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]2)[C:8]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Oc3cc(F)c(Br)cc3F)C2=O)CC1
Reactant: CS(=O)[O-]
Agent: N[C@H]1CCCC[C@@H]1N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Oc3cc(F)c(S(C)(=O)=O)cc3F)C2=O)CC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 43.6 %

Procedure:
A suspension of (S)-tert-butyl 3-(4-bromo-2,5-difluorophenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (700 mg, 1.39 mmol), and sodium methanesulfinate (219 mg, 2.08 mmol) in DMSO (5.55 mL), was deoxygenated and purged with nitrogen. Cu(I) triflate benzene complex (77.6 mg, 0.139 mmol) and (1S,2S)-cyclohexane-1,2-diamine (63.4 mg, 0.555 mmol) were introduced and the heterogeneous mixture was sealed and heated to 110° C. in an oil bath and stirred for 18 hours. The mixture was cooled to ambient temperature, diluted with EtOAc (75 mL), washed with water (30 mL) and brine (three 50 mL washes), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified over silica gel (EtOAc) to afford (S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (305 mg, 0.606 mmol, 44% yield) as a light yellow oil that solidified. Mass spectrum (apci) m/z=389.1 (M+H-Boc).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([O:14]C)[CH:11]=[C:10]([O:16]C)[CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl.C(=O)=O.CC(C)=O>[CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([OH:16])[CH:11]=[C:12]([OH:14])[CH:13]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(OC)cc(C(=O)C2CCCC2)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(c1cc(O)cc(O)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of cyclopentyl-(3,5-dimethoxy-phenyl)-methanone (234 mg) in anhydrous dichloromethane (5 mL) cooled in dry ice/acetone bath was added dropwise a solution of boron tribromide (4 mL of 1 M solution in dichloromethane). After the addition was completed, the cooling bath was removed and the reaction mixture was stirred at room temperature overnight. Unreacted boron tribromide was quenched with methanol. Then the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 200 mg of the title compound (97% yield). Note: the title compound decomposes on air. HRMS calcd for C12H14O3 [M+H]+ 207.1016, observed 207.1016.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>O1CCCC1>[CH3:1][N:2]1[CH:3]=[C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]1=[O:8]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: C1COCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N2CCOCC2)cc1
Yield: 105.6 %

Procedure:
A mixture 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (60 mg), morpholine (17 mg), benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate (108 mg, BOP reagent) and N-ethyldiisopropylamine (62 mg) in tetrahydrofuran (0.6 ml) was stirred overnight at room temperature. The mixture was concentrated to dryness. The product was purified by chromatography (SiO2, dichloromethane/methanol 1:0 to 9:1) to give the title compound (75 mg) as a colorless foam, MS (ESI+): m/z=445.4 [M+H]+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH2:8]1.[C:28]1([NH2:39])C(F)=C(F)C(F)=C(N)[C:29]=1F.Cl.Cl.S(Cl)(Cl)=[O:43]>>[OH:43][CH2:29][CH2:28][NH:39][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([CH2:14][CH2:13][N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=3[Cl:3])[CH2:8][CH2:9]2)=[CH:16][CH:17]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: O=S(Cl)Cl
Reactant: O=C(Cl)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1
Agent: Cl
Product: O=C(NCCO)c1ccc(CCN2CCN(Cc3ccccc3Cl)CC2)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 11.0 g. (24.4 mmole) 4-{2-[1-(2-chlorobenzyl)-piperazin-4-yl]-ethyl}-benzoyl chloride dihydrochloride (prepared from the dihydrochloride of the acid by boiling for 3 hours with excess thionyl chloride, evaporating and digesting with ligroin; yield 98% of theory; m.p. 260° C.) and 10 ml. anhydrous pyridine there are added, with stirring at 20° C., 10 ml. ethanolamine and the reaction mixture is left to stand overnight and then poured into about 100 ml. water. The precipitate obtained is washed with an aqueous solution of sodium bicarbonate and with water, dried and then recrystallised from aqueous ethanol. There is obtained a yield of the desired product of 5.0 g. (51% of theory); m.p. 121°-122° C.
Reaction SMILES: [CH:1]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][CH:4]=[C:3]([I:11])[CH:2]=1.[CH2:12]([NH2:14])[CH3:13].C(N(CC)CC)C>ClCCl.C1COCC1>[CH2:12]([NH:14][S:7]([C:6]1[CH:5]=[CH:4][C:3]([I:11])=[CH:2][CH:1]=1)(=[O:9])=[O:8])[CH3:13]
Reactant: CCN
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNS(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pipsyl chloride 25 g was dissolved in dichloromethane 250 ml to which was added a solution of ethyl amine 2M, in THF 42 ml and triethylamine 9 g in dichloromethane 100 ml over 30 min. The mixture was stirred a further 1 h at room temperature and then washed with water and 1N hydrochloric acid, dried (MgSO4) and evaporated in vacuo to give N-ethyl-4-iodo-benzenesulfonamide as a white solid, 26.2 g. 1H NMR 7.88 (2H, d), 7.59 (2H, d), 4.65 (1H, m), 3.01 (2H, m), 1.11 (3H, t).
Reaction SMILES: [N:1](=[C:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4]#[N:5])[OH:2].Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>C(O)C>[N:1](=[C:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4](=[N:13][OH:14])[NH2:5])[OH:2]
Reactant: NO
Reactant: N#CC(=NO)c1cccnc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NC(=NO)C(=NO)c1cccnc1

Procedure:
A mixture of alpha-oximino-3-pyridylacetonitrile (41.0 g, 279 mmol). hydroxylamine hydrochloride (21.5 g, 310 mmol) and sodium acetate (50.8 g, 620 mmol) in ethanol (99.9%, 500 ml) was refluxed for 4 h. After cooling, the precipitate was collected by filtration and dried. The precipitate contained the wanted product and sodium acetate (85 g, 168%); M+ : 180.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:20])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Cl:16])[CH2:12][C:11]([CH2:18][CH3:19])([CH3:17])[CH2:10]2>O.CO>[CH2:18]([C:11]1([CH3:17])[CH2:10][C:9]2[C:13](=[CH:14][C:15]([Cl:16])=[C:7]([CH2:6][C:5]([OH:20])=[O:4])[CH:8]=2)[CH2:12]1)[CH3:19]
Reactant: CCC1(C)Cc2cc(Cl)c(CC(=O)OC)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC1(C)Cc2cc(Cl)c(CC(=O)O)cc2C1

Procedure:
A solution of 20 g of potassium hydroxide in 40 cc of water is added to a solution of 11.5 g of 2-ethyl-6-chloro-2-methyl-5-indanacetic acid methyl ester in 250 cc of methanol, and the solution is boiled at reflux for one hour. The cooled solution is concentrated, diluted with water and the neutral components are extracted with ether. The aqueous phase is acidified with hydrochloric acid, extracted with ether, the ether extract is washed with water, dried over sodium sulphate and concentrated by evaporation. The resulting 2-ethyl-6-chloro-2-methyl-5-indanacetic acid is recrystallized from hexane and has a M.P. of 87°-89°.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[O-:5])[CH3:2].[OH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>>[CH2:1]([NH:3][C:4](=[O:5])[O-:6])[CH3:2].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH:12]([CH3:20])[CH:13]4[CH2:17][NH:16][CH2:15][CH:14]4[C:18]=3[CH:19]=2)=[CH:24][CH:23]=1
Reactant: CC1c2ccc(O)cc2C2CNCC12
Reactant: Fc1ccc(CBr)cc1
Agent: CCNC(=O)[O-]
Product: CC1c2ccc(OCc3ccc(F)cc3)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 43, Step B utilizing N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 43, Step A) (0.1 mmol) and 4-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C22H24FNO3+H: 370, observed: 370.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])[CH:5]=[C:4](Cl)[N:3]=1.[Si:19]([O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Si:19]([O:26][CH:27]1[CH2:28][CH2:29][N:30]([C:4]2[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=3)[CH3:10])[CH:5]=2)[CH2:31][CH2:32]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: C[C@H](Nc1cc(Cl)nc(Cl)n1)c1ccc(F)cn1
Reactant: CC(C)(C)[Si](C)(C)OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](Nc1cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)nc(Cl)n1)c1ccc(F)cn1
Temperature: 130 °C
Yield: 49.2 %

Procedure:
A mixture of 2,6-dichloro-N-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]pyrimidin-4-amine (Preparation 10a, 0.66 g, 2.31 mmol), 4-(tert-butyl-dimethylsilanyloxy)piperidine (prepared as described in WO2004/006926, 0.60 g, 2.77 mmol) and cesium carbonate (1.13 g, 3.46 mmol) in N,N′-dimethylformamide (15 mL) was stirred and heated to 130° C. in a sealed tube for 2 hours. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate (×3). The combined organic extract was washed with water and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes to 6:4 hexanes/ethyl acetate) to give the title compound (0.53 g, 50%) as a white solid.
Reaction SMILES: [Na].[C:2]1([CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1)[OH:3].Cl[CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14].[Cl-].[NH4+]>O.CN(C)C=O>[CH3:14][O:13][CH:12]([O:15][CH3:16])[CH2:11][O:3][C:2]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: Oc1ccc(O)cc1
Reactant: COC(CCl)OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1ccc(O)cc1)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The monosodium salt of hydroquinone prepared in Example 1 and dimethyl formamide (100 ml) were charged under nitrogen gas into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel and were warmed to effect dissolution. The resulting solution was then allowed to warm to room temperature, and 1-chloro-2,2-dimethoxyethane was added dropwise over a period of about 20 minutes. After the addition was completed, the reaction mixture was heated at about 85° to 90° C. with stirring for a period of about 48 hours. After this time water (200 ml) was added, and the reaction mixture was neutralized with ammonium chloride. The reaction mixture was then extracted with chloroform, and the organic phase was separated from the aqueous phase. The organic phase was then stripped of solvent, leaving a red oil. This oil was distilled to yield the desired product 4-(2,2-dimethoxyethoxy)phenol as a pink oil boiling at 116° to 120° C. at 0.008 mm of Hg pressure.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]([CH3:9])([OH:8])[CH3:7])[CH2:3][OH:4].[N:10]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[OH:4][CH2:3][C@@H:2]([NH:1][C:16]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:17])[CH2:5][C:6]([OH:8])([CH3:9])[CH3:7]
Reactant: CC(C)(O)C[C@H](N)CO
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)C[C@@H](CO)NC(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(S)-2-amino-4-methylpentane-1,4-diol (0.6 g, 4.5 mmol) was dissolved in anhydrous dichloromethane (10 mL) and the solution was cooled to 0° C. Next, 4-morpholinecarbonyl chloride (0.78 mL, 6.75 mmol) was added, followed by triethylamine (0.75 mL, 5.4 mmol). The reaction was stirred for 3 hrs at 0-5° C. The solvent was evaporated and the residue was purified using silica gel chromatography (10% methanol-dichloromethane) to afford Cmpd 66. Yield: 0.675 g (61%). MS (m/z): (M+H)=247.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CO.[NH3:13]>>[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[NH4+:13]
Reactant: N
Reactant: Nc1ccccc1C(=O)O
Solvent: CO
Product: Nc1ccccc1C(=O)[O-]
Product: [NH4+]
Reaction time: 2 h
Yield: 94 %

Procedure:
In a 50 mL volume glass vessel equipped with a stirrer and a thermometer were placed 5.0 g (36.5 mmol) of anthranilic acid and 20 mL (156 mmol) of 15 wt. % ammonia methanol solution. The reaction was carried out for 2 hours at room temperature. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, to obtain 5.0 g (isolated yield: 94%) of ammonium anthranilate as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:12](O)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[NH:19]=[N+:20]=[N-:21].C(P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(=O)=O>C1(C)C=CC=CC=1.C1COCC1>[N:19]([C@@H:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=N
Reactant: CCOc1cc([C@@H](O)CS(C)(=O)=O)ccc1OC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N=[N+]=[N-])ccc1OC
Reaction time: 16 h
Yield: 81 %

Procedure:
A mixture of (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanol (0.94 g, 3.4 mmol) in toluene (280 mL) and THF (20 mL) was sparged with nitrogen for 15 min, and then a ˜1.1 M solution of hydrazoic acid in toluene (13.8 mL, ˜15 mmol) was added. The flask was cooled in a dry ice-acetone bath. When the internal temperature reached <−60° C., tributylphosphine (1.7 mL, 6.9 mmol), and then diisopropyl azodicarboxylate (1.6 mL, 7.9 mmol) were added. The cooling bath was charged with dry ice for the next 4 h in order to maintain the reaction temperature at <−60° C., and then the temperature was allowed to gradually rise. After 16 h, the internal temperature had climbed to −2° C. Then, silica gel (20 g) was added and the resulting slurry was evaporated. The residue was chromatographed on a silica gel column, using a hexanes-EtOAc gradient. After pooling and evaporating the appropriate fractions, the residue was triturated with heptane (25 mL) and the slurry was filtered. Solids were dried under vacuum, to provide (S)-4-(1-azido-2-(methylsulfonyl)ethyl)-2-ethoxy-1-methoxybenzene as a white solid (0.84 g, 81% yield); HPLC (Hypersil BDS C8, 5.0 μm, 250×4.6 mm, 1.5 mL/min, 278 nm, 90/10 gradient to 80/20 0.1% aqueous TFA/MeOH over 10 min then gradient to 10/90 0.1% aqueous TFA/MeOH over the next 15 min): 17.77 (99.9%); 1H NMR (DMSO-d6) δ 1.33 (t, 3H), 2.99 (s, 3H), 3.55 (dd, J=4.0, 14.7 Hz, 1H), 3.77 (s, 3H), 3.90 (dd, J=9.6, 14.7 Hz, 1H), 3.98-4.13 (m, 2H), 5.01-5.21 (m, 1H), 6.90-7.05 (m, 2H), 7.08 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6][N:7]2[CH:18]1[CH2:20][CH2:19]1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][CH2:32][CH2:33][NH2:34].C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:34][CH2:33][CH2:32][NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)[C:9]([O:14][CH:15]([CH3:16])[CH3:17])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6][N:7]2[CH:18]1[CH2:19][CH2:20]1
Reactant: NCCNc1ccccn1
Reactant: CC(C)Oc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)Oc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A solution of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-4-oxoquinoline-3-carboxylic acid (100 mg, 0.296 mmol), N-2-pyridyl-1,2-ethanediamine (60.9 mg, 0.444 mmol) and triethylamine (0.0619 mL, 0.444 mmol) in DMSO (3 mL) was stirred at 100° C. for 8 h. After the reaction mixture was poured into ice-water, NH4Cl was added and stirred for 30 min. The resulting precipitate was collected by filtration in vacuo and washed with water. The crude product was purified by preparative thin layer chromatography (Hexane:EtOAc 1:4) to yield 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-isopropoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (80.6 mg, 60%) as a pale yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Si:20]([O:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42]O)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(C=P(CCCC)(CCCC)CCCC)#N.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:20]([O:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH:11]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([C:33]([CH3:35])([CH3:36])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)[Si](OCCSCCO)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCSCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Yield: 94.9 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (900 mg, 2.97 mmol) obtained in Example 5 and 2-[2-(t-butyldiphenylsilyloxy)ethylthio]ethanol (1.64 g, 4.55 mmol) were dissolved in toluene (20 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (1.26 g, 5.22 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 9 hours. After the reaction mixture was allowed to cool down, 2-[2-(t-butyldiphenylsilyloxy)ethylthio]ethanol (500 mg, 1.39 mmol) and cyanomethylenetri-n-butylphosphorane (400 mg, 1.66 mmol) were added thereto. Under an argon atmosphere, the mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, it was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane:ethyl acetate=10:1 eluate was concentrated under reduced pressure, whereby the title compound (1.82 g, 2.82 mmol, 95%) was obtained as a pale yellowish brown oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](I)[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:20])[CH2:16][CH2:15][C:14](B(O)O)=[CH:13][CH2:12]1.C([O-])([O-])=O.[Na+].[Na+]>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>[Br:1][C:2]1[N:7]=[C:6]([C:14]2[CH2:15][CH2:16][C:11]([CH3:20])([CH3:10])[CH2:12][CH:13]=2)[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nc1I
Reactant: CC1(C)CC=C(B(O)O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1(C)CC=C(c2nc(Br)ccc2N)CC1

Procedure:
The title compound was prepared from 6-bromo-2-iodo-pyridin-3-ylamine (as prepared in the previous step, 348 mg, 1.17 mmol), 4,4-dimethylcyclohexen-1-yl boronic acid (198 mg, 1.28 mmol), Pd(PPh3)4 (135 mg, 0.117 mol) and 2M Na2CO3 (15.2 mL, 30.5 mmol) according to the procedure in Example 34, step (b) (417 mg, 46%). 1H-NMR (CDCl3; 400 MHz): δ 7.06 (d, 1H, J=8.3 Hz), 6.85 (d, 1H, J=8.3 Hz), 5.95 (m, 1H), 3.86 (br s, 2H), 2.43-2.39 (m, 2H), 1.99-1.97 (m, 2H), 1.51 (t, 2H, J=6.4 Hz), 0.99 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][CH:12]([NH2:14])[CH3:13].Cl.Cl.C[Si](C)(C)CCOC[N:23]1[C:27]2[N:28]=[CH:29][N:30]=[C:31]([C:32]3[CH:33]=[N:34][N:35]([C:37]4([CH2:41][C:42]#[N:43])[CH2:40][NH:39][CH2:38]4)[CH:36]=3)[C:26]=2[CH:25]=[CH:24]1>>[C:42]([CH2:41][C:37]1([N:35]2[CH:36]=[C:32]([C:31]3[C:26]4[CH:25]=[CH:24][NH:23][C:27]=4[N:28]=[CH:29][N:30]=3)[CH:33]=[N:34]2)[CH2:40][N:39]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH:14][CH:12]([CH3:13])[CH3:11])=[O:10])=[N:6][CH:7]=2)[CH2:38]1)#[N:43]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: CC(C)N
Reactant: O=C(O)c1ccc(Br)cn1
Agent: Cl
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 3, Step 1-3 starting from 5-bromopyridine-2-carboxylic acid, 2-propanamine and {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride. LCMS (M+H)+: m/z=442.2. 1H NMR (400 MHz, DMSO-d6): δ 12.82 (s, 1H), 9.12 (s, 1H), 8.88 (s, 1H), 8.59 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.83 (m, 1H), 7.28 (m, 1H), 7.10 (dd, J=8.0, 3.0 Hz, 1H), 4.66 (d, J=8.0 Hz, 2H), 4.41 (d, 7=8.0 Hz, 2H), 3.78 (s, 2H), 4.05 (m, 1H), 1.16 (d, J=6.5 Hz, 6H).
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:32]=[CH:31][CH:30]=[CH:29][C:6]=1[CH2:7][S:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[C:15]([N:19]3[C:23](=[O:24])[N:22]([CH:25]([F:27])[F:26])[C:21]([CH3:28])=[N:20]3)=[CH:14][C:12]=2[N:13]=1.ClC1C=C(C=CC=1)C(OO)=[O:38].[OH2:44]>>[Cl:4][C:5]1[CH:32]=[CH:31][CH:30]=[CH:29][C:6]=1[CH2:7][S:8]([C:9]1[S:10][C:11]2[CH:17]=[C:16]([Cl:18])[C:15]([N:19]3[C:23](=[O:24])[N:22]([CH:25]([F:26])[F:27])[C:21]([CH3:28])=[N:20]3)=[CH:14][C:12]=2[N:13]=1)(=[O:38])=[O:44]
Reactant: Cc1nn(-c2cc3nc(SCc4ccccc4Cl)sc3cc2Cl)c(=O)n1C(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Solvent: ClCCl
Product: Cc1nn(-c2cc3nc(S(=O)(=O)Cc4ccccc4Cl)sc3cc2Cl)c(=O)n1C(F)F
Reaction time: 0.17 h
Yield: 90 %

Procedure:
10 mL dichloromethane was charged with 0.001 mol 1-(2-(2-chlorobenzylthio)-6-chlorobenzo[d]thiazol-5-yl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred for 10 mins and then 0.002 mol m-chloroperoxybenzoic acid (MCPBA) were added. After stirring at room temperature for 4 hours, the mixture was poured into 30 mL of water, then extracted with 15 mL dichloromethane twice. Organic phases were combined and dried over anhydrous sodium sulfate. Filtration and removal of solvent under vacuum gave the title compound as a white solid in a 90% yield.