Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [B-](F)(F)(F)CN1CCCC1.[K+].[F:12][C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][CH:19]([C:22]3[CH:34]=[CH:33][C:25]([CH2:26][N:27]4[CH2:32][CH2:31]O[CH2:29][CH2:28]4)=[CH:24][CH:23]=3)[O:18][C:17]=2[CH:35]=1>>[F:12][C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][CH:19]([C:22]3[CH:23]=[CH:24][C:25]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:29][CH2:28]4)=[CH:33][CH:34]=3)[O:18][C:17]=2[CH:35]=1
Reactant: Fc1ccc2c(c1)OC(c1ccc(CN3CCOCC3)cc1)CO2
Agent: F[B-](F)(F)CN1CCCC1
Agent: [K+]
Product: Fc1ccc2c(c1)OC(c1ccc(CN3CCCC3)cc1)CO2

Procedure:
The title compound is prepared from G-4 and Potassium 1-trifluoroboratomethylpyrrolidine according to the procedure described for the synthesis of compound 202. 203: LC/MS Method 10; Rt=1.07 min.; [M+H]+=354.4.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:34][CH2:35][CH:36]([OH:39])[CH2:37][CH3:38]>ClCCl>[OH:39][CH:36]([CH2:37][CH3:38])[CH2:35][NH:34][C:14]([CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CCC(O)CN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(O)CNC(=O)CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
23.20 g (103.93 mmol) 3-benzyloxycarbonylamino-propionic acid, 14.10 g (104.35 mmol) 1-hydroxybenzotriazole, 18.80 ml (135.07 mmol) triethylamine and 21.00 g (135.27 mmol) (ethyl-3-(3-dimethylamino)-propylcarbondiimide hydrochloride (EDAC) are placed in 150 ml dichloromethane, cooled to 0° C. and stirred for 0.75 hours at this temperature. Then 10.50 g (114.26 mmol) 1-amino-2-butanol are added, the mixture is stirred for 2.5 hours at 0°-5° C. The reaction mixture is extracted with water and 1 molar sodium carbonate solution, the organic phase is dried and evaporated to dryness. The residue is extracted again with dichloromethane and sodium carbonate solution.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([CH2:39][C:40]([CH3:48])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH3:41])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:49])[N:20]([CH2:39][C:40]([CH3:48])([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH3:41])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(CC(C)(C)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(CC(C)(C)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.27 g), sodium hydrogen carbonate (0.45 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-1-(2-methyl-2-phenylpropyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.13 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.052 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.044 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.036 g, 24%).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14]Br)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:16]1([CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=1)[OH:17].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][O:17][C:16]2[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](CCCBr)CC1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCC[C@H]1CC[C@H](CCCOc2ccc(O)cc2)CC1
Yield: 52.4 %

Procedure:
A mixture of 5.0 g of 3-(trans-4-pentylcyclohexyl)-1-propyl bromide, 10.0 g of hydroquinone, 10.0 g of anhydrous potassium carbonate and 250 ml of absolute butanone was heated under reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 100 ml of dichloromethane each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulfate, filtered and concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 4:1) gave 2.9 g of 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]phenol; m.p. 100°-101° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:37]>>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[O:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)o1
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)o1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-oxazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (94 mg, 0.179 mmol) and ammonium hydroxide (5 mL), the title compound was obtained as a white solid (30 mg, 33%). 1H-NMR (DMSO-d6): δ ppm 10.34 (brs, 1H), 8.18-8.19 (d, J=5.2 Hz, 1H), 7.65 (brs, 1H), 7.30-7.34 (t, J=7.4 Hz, 2H), 7.21-7.24 (m, 3H), 6.56 (brs, 2H), 6.45 (d, J=5.2 Hz, 1H), 1.40 (s, 9H); MS: 504 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].C(N(CC)CC)C.[CH2:22]([OH:25])[CH2:23][CH3:24]>>[OH:13][C:12]1[C:3]([CH2:2][O:25][CH2:22][CH2:23][CH3:24])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:14])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Reactant: CCCO
Solvent: CCN(CC)CC
Product: CCCOCc1c(O)ccc2c1CCCC2=O

Procedure:
According to step 1 in the method of example 19a, 5-Chloromethyl-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.211 g, 1.0 mmol) was combined with triethylamine (0.167 ml, 1.2 mmol) in propan-1-ol (3.0 ml, Aldrich Chemical) to produce 123 mg of desired product as yellow crystals. Low resolution mass spectrum (APCI) m/z 235 [M+H]+.
Reaction SMILES: [CH:1](=[C:3]1[C:9](=[O:10])[N:8]2[CH:4]1[CH2:5][C:6]([S:24][CH2:25][CH2:26][NH:27]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)=[C:7]2[C:11]([O:13]CC1C=CC([N+]([O-])=O)=CC=1)=[O:12])[CH3:2].C1COCC1>O=[Pt]=O.CCO>[CH2:1]([CH:3]1[C:9](=[O:10])[N:8]2[CH:4]1[CH2:5][C:6]([S:24][CH2:25][CH2:26][NH2:27])=[C:7]2[C:11]([OH:13])=[O:12])[CH3:2]
Reactant: CC=C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)CC12
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCC1C(=O)N2C(C(=O)O)=C(SCCN)CC12
Reaction time: 2.5 h

Procedure:
A mixture of p-nitrobenzyl 6-ethylidene-3-[2-(p-nitrobenzyloxycarbonylamino)ethylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (37 mg), PtO2 (40 mg), THF (4 ml) and EtOH (2 ml) is hydrogenated at 50 psi and 25° C., for 2.5 hrs. The catalyst is filtered off and washed thoroughly with 0.1 M pH 7 phosphate buffer (5 ml). The combined filtrate and washings are concentrated in vacuo to remove most of the organic solvents. The aqueous residue is chromatographed on a column of Dowex-50×4 (Na Form) ion-exchange resin; the product being eluted with deionized H2O. The appropriate fractions are combined and lyophilized to afford 6-ethyl-3-(2-aminoethyl)thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[CH:4][CH:3]=1.ClC1C=CN=[C:21]([C:25]([NH:27][CH3:28])=[O:26])C=1>>[CH3:28][NH:27][C:25]([CH2:21][NH:15][C:13]([C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1)=[O:14])=[O:26]
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: CNC(=O)c1cc(Cl)ccn1
Product: CNC(=O)CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)-pyridine-2-carboxamide, substituting of 4-chloropyridine-2-carboxylic acid N-methylcarbamoylmethylamide for 4-chloro-N-methyl-pyridine-2-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCN(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Yield: 92.6 %

Procedure:
A solution of 1,1-dimethylethyl 4-{4-[3-(methyloxy)-4-nitrophenyl]-1-piperazinyl}-1-piperidinecarboxylate (5.67 g, 13.5 mmol) and DCM (110 mL) was cooled with an ice/H2O bath. TFA (30.0 mL, 389 mmol) was added dropwise via addition funnel. Upon completion, by TLC, the reaction mixture was quenched with 1N NaOH (300 mL), extracted with DCM, dried (MgSO4) and concentrated to provide the title compound of step D (4.01 g, 12.5 mmol, 93%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.31 (m, 2H), 1.68 (d, J=9.9 Hz, 2H), 2.22-2.32 (m, 2H), 2.34-2.45 (m, 2H), 2.54-2.61 (m, 4H), 2.95 (d, J=12.1 Hz, 2H), 3.36-3.43 (m, 4H), 3.88 (s, 3H), 6.50 (d, J=2.6 Hz, 1H), 6.57 (dd, J=9.4, 2.4 Hz, 1H), 7.86 (d, J=9.5 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:4]=[C:3]1[C:18]([OH:20])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:34][O:35][NH:36][CH3:37].CCN(C(C)C)C(C)C>C1COCC1.O>[CH3:34][O:35][N:36]([CH3:37])[C:18]([C:3]1[C:2](=[O:1])[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[N:4]=1)=[O:20]
Reactant: O=C(O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CON(C)C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 40 °C
Reaction time: 20 h
Yield: 104.2 %

Procedure:
A mixture of 4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylic acid (2.00 g, 7.04 mmol) and CDI (1.26 g, 7.74 mmol) in THF (20 mL) was heated to 40° C. for 2 h. To the solution were added N-methoxymethanamine hydrochloride (1.03 g, 10.6 mmol) and i-Pr2NEt (1.84 mL, 10.6 mmol) at room temperature. The solution was stirred at room temperature for 20 h. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 80/20) to yield the crude title compound (2.40 g) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.28 (3H, s), 3.61 (3H, s), 6.67 (1H, d, J=7.9 Hz), 7.77-7.90 (2H, m), 8.00-8.14 (2H, m), 8.99 (1H, d, J=7.9 Hz).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl.CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][O:25]1
Reactant: C1=COCCC1
Reactant: OCCCCCBr
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: BrCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 5-bromopentanol (10 g) in DCM (150 mL) was added pyridinium p-toluenesulfonate (1.5 g) followed by 3,4-dihydro-2H-pyran (8.1 mL) and the reaction mixture was stirred at room temperature under nitrogen for 21 hours. The solution was diluted with ether then washed with diluted brine (1:1 brine:water, 140 mL) before the organics were dried over sodium sulfate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0 to 50% ethyl acetate in cyclohexane to afford the subtitled compound as a colourless liquid. Yield 14.14 g.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[N:11][CH:12]=1.[CH3:20][C:21]1([CH3:32])[C:25]([CH3:27])([CH3:26])[O:24][B:23](OC(C)C)[O:22]1>C1COCC1>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([B:23]2[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:32])([CH3:20])[O:22]2)=[CH:12][N:11]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CN(C)CCCOc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 18 °C
Reaction time: 4 h
Yield: 11 %

Procedure:
Butyllithium (2.5N, 4.8 mL, 50.96 mmol) was added to a solution of 3-(5-bromopyridin-2-yl)oxy-N,N-dimethylpropan-1-amine (2.07 g, 7.99 mmol) and 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (2.79 g, 15.00 mmol) in THF (20 mL) at −78° C. over 10 minutes under an inert atmosphere. The resulting solution was stirred for 4 h at 18° C. The reaction was then quenched by the addition of a sat. aqueous solution of ammonium chloride then partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was concentrated in vacuo and the residue purified by FCC, eluting with EtOAc/petroleum ether (1:3) to afford the desired material (270 mg, 11%) as a yellow solid. Mass Spectrum: m/z (ES+)[M+H]+=225.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([O:17]CC)=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:20]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]([NH2:14])=[O:20])=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(Br)c2)c1C#N
Reactant: [OH-]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1cccc(Br)c1

Procedure:
A 14 g. portion of ethyl 1-(3-bromophenyl)-5-cyano-4-pyrazolecarboxylate was hydrolyzed by stirring under reflux in 200 ml. of ethanol with 6 g. ofpotassium hydroxide for 2 hours. The mixture was then poured over ice, acidified and filtered, and the solids were crystallized from ethanol/water and dried at 168° to obtain 10 g. of the desired product, m.p. 215°-217° dec. The product was identified by NMR analysis in CDCl3 /DMSOd6. δ7.06 (s, 1), carboxamide; 7.30-7.64 (m, 4), aromatic; 8.08 (s, 1), pyrazole; 9.10 (s, 1), carboxamide.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([O:37][CH3:38])[CH2:36][O:35][CH2:34]2)[CH:30]=[C:29]([F:39])[C:28]=1[C:40]1[N:45]=[C:44]([C:46](O)=[O:47])[CH:43]=[CH:42][C:41]=1[F:49]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:46](=[O:47])[C:44]2[CH:43]=[CH:42][C:41]([F:49])=[C:40]([C:28]3[C:29]([F:39])=[CH:30][C:31]([C:33]4([O:37][CH3:38])[CH2:36][O:35][CH2:34]4)=[CH:32][C:27]=3[F:26])[N:45]=2)[CH2:6][CH2:7]1
Reactant: COC1(c2cc(F)c(-c3nc(C(=O)O)ccc3F)c(F)c2)COC1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: COC1(c2cc(F)c(-c3nc(C(=O)Nc4cnn(C)c4[C@@H]4CC[C@@H](N)[C@H](F)CO4)ccc3F)c(F)c2)COC1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(3-methoxyoxetan-3-yl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 202. 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.32 (dd, J=8.7, 4.0 Hz, 1H), 8.17 (t, J=8.9 Hz, 1H), 7.94 (s, 1H), 7.42 (d, J=9.3 Hz, 2H), 4.87-4.75 (m, 5H), 4.17 (ddt, J=49.0, 6.1, 2.6 Hz, 1H), 4.03-3.84 (m, 2H), 3.75 (s, 3H), 3.14 (s, 3H), 3.12-2.98 (m, 1H), 2.11-2.00 (m, 1H), 1.80-1.57 (m, 3H). LCMS (ES+) m/z 550 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:5](O)=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:5]2[S:18][C:17]([NH:19][CH:2]3[CH2:3][CH2:4][CH2:8][CH2:9][CH2:10]3)=[N:16][N:15]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: NNC(N)=S
Reactant: COc1ccc(Cl)c(OC)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cl)c(OC)c1-c1nnc(NC2CCCCC2)s1
Temperature: 95 °C
Yield: 28.3 %

Procedure:
To a mixture of 3-chloro-2,6-dimethoxybenzoic acid (2.3 mmol, 500 mg), thiosemicarbazide (5b) (2.3 mmol, 399 mg) in anhydrous dioxane (10 mL) at 70° C. to 80° C., POCl3 (2.3 mmol, 215 μL) was added, and the mixture was warmed at 95° C. for 5 hours. The solvent was removed by distillation under reduced pressure to give a crude material which was basified at pH 8-7 with a saturated solution of NaHCO3. The precipitate obtained was collected by filtration, washed with water, and dried under vacuum. The solid was subjected to flash chromatography eluting with ethyl acetate/cyclohexane to give 115 mg of the title compound. Yield: 14%.
Reaction SMILES: [CH:1]12[CH2:9][CH:6]3[CH:7]([CH2:8]1)[CH:3]([O:4][CH:5]3[OH:10])[CH2:2]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:10][CH:5]1[CH:6]2[CH2:9][CH:1]3[CH2:8][CH:7]2[CH:3]([CH2:2]3)[O:4]1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: OC1OC2CC3CC1C2C3
Solvent: c1ccncc1
Product: CC(=O)OC1OC2CC3CC2C1C3
Temperature: 50 °C
Yield: 87.9 %

Procedure:
A mixture of 14 g of 4-oxatricyclo[4.2.1.03,7]nonan-5-ol, 12 g of pyridine and 14 g of acetic anhydride was heated at 50° C. for 5 hours. The reaction mixture was concentrated. The concentrate was purified by distillation, obtaining 16 g (yield 88%) of the target compound.
Reaction SMILES: C(O[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[N:18]=[N:19][C:20]([Cl:32])=[CH:21][C:22]=2[O:23]C(=O)C2C=CC=CC=2)=[C:12](C)[CH:11]=1)(=O)C1C=CC=CC=1.ClCCl.[CH2:37]([N:39](CC)CC)[CH3:38].C(Cl)(=[O:46])C>[Cl-].[Na+].O>[Cl:32][C:20]1[N:19]=[N:18][C:17]([O:16][C:13]2[CH:14]=[CH:15][CH:10]=[CH:11][C:12]=2[NH:39][C:37](=[O:46])[CH3:38])=[C:22]([OH:23])[CH:21]=1
Reactant: Cc1cc(OC(=O)c2ccccc2)ccc1Oc1nnc(Cl)cc1OC(=O)c1ccccc1
Reactant: CCN(CC)CC
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccccc1Oc1nnc(Cl)cc1O
Yield: 17.1 %

Procedure:
18.0 mg (0.0756 mmol) of 3-(2-aminophenoxy)-3-chloro-4-pyridazinol obtained in Example 641 was mixed with dichloromethane (0.8 mL), 0.050 mL (0.36 mmol) of triethylamine, then 0.010 mL (0.14 mmol) of acetyl chloride were added to the mixture in an ice bath with stirring, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into brine, and extracted with tetrahydrofuran. The organic layers were combined, washed with brineand dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO., 1.05715, developed by dichloromethane:methanol=10:1) to obtain 3.6 mg (0.0129 mmol, Yield: 17.1%) of N-{2-[(6-chloro-4-hydroxy-3-pyridazinyl)oxy]phenyl}acetamide (Compound No. 380).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:26]=1)[CH3:2].C(OO)(=[O:36])C.C(O)(=O)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C.O>[CH2:1]([C:3]1[N:4]([CH2:27][CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[CH:10][C:9]=3[N+:8]([O-:36])=[CH:7][C:6]=2[N:26]=1)[CH3:2]
Reactant: CC(=O)OO
Reactant: CCc1nc2cnc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC1CCOCC1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCc1nc2c[n+]([O-])c3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC1CCOCC1
Temperature: 50 °C

Procedure:
tert-Butyl 2-{[2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate (2.3 g, 5.06 mmol) was slurried in ethyl acetate (20 mL). 32% Peracetic acid in acetic acid (1.06 mL, 5.06 mmol) was added in one portion and the reaction was heated to 50° C. for 2 hours. Another 0.250 mL (1.19 mmol) peracetic acid solution was added and the reaction was stirred for 1 additional hour. Sodium metabisulfite (1.2 g, 6.33 mmol) in water (2.5 mL) was added over 3 minutes and the reaction was stirred for 30 minutes. The heat was removed and the reaction was brought to pH 10 with saturated aqueous sodium carbonate (˜10 mL). The milky slurry was cooled in an ice bath and subsequently filtered. The solid was washed with water and dried for 1 hour. Roughly 2.0 g of tert-butyl 2-{[2-ethyl-5-oxido-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate was isolated as an off-white solid with water still remaining.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.[OH-].[Na+]>CCOC(C)=O.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:13]([C:12]3[CH:16]=[CH:17][C:18]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:19][C:11]=3[F:10])=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nc3cc(Br)ccc3o2)c(F)c1
Temperature: 195 °C
Yield: 80.5 %

Procedure:
2-Amino-4-bromophenol (1.77 g, 9.4 mmol) and 2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.4 mmol) were dissolved in polyposphoric acid (60 g). This mixture was heated at 195° C. for three and half hours. Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (EtOAc/H2O) followed by evaporation of EtOAc afforded the crude. Crude was purified on combiflash with a gradient mixture of EtOAc and Petether (33:67) to obtain the titled compound (2.8 g) as an off-white solid.