Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@:3]1([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:7]([OH:9])=O.[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][NH2:30])=[N:27][CH:28]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][NH:30][C:7]([C@:3]2([CH2:10][O:11][Si:12]([CH:13]([CH3:14])[CH3:15])([CH:16]([CH3:17])[CH3:18])[CH:19]([CH3:20])[CH3:21])[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[O:9])=[N:27][CH:28]=1
Reactant: CC(C)[Si](OC[C@@]1(C(=O)O)CCCN1C)(C(C)C)C(C)C
Reactant: NNc1ccc(F)cn1
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: ClCCl
Product: CC(C)[Si](OC[C@@]1(C(=O)NNc2ccc(F)cn2)CCCN1C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of Intermediate 85g (1.08 g, 3.58 mmol), (5-fluoro-pyridin-2-yl)-hydrazine (500 mg, 3.93 mmol) and DIPEA (1.38 g, 10.7 mmol) in DCM (120 mL) was added HATU (2.04 g, 5.37 mmol) and the mixture stirred at RT for 2 h. The solution was washed with 10% aq. K2CO3 solution, brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by FCC, using 0-6% [2M NH3 in MeOH] in DCM, to give the title compound as a pale yellow oil (1.37 g, 90%). LCMS (Method 4): Rt 2.74 min, m/z 425 [MH+].
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[I-].[Na+].[C:34](=[O:37])([O-])[O-:35].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][N:19]3[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[C:7]([C:11]([O:13][CH:14]([O:35][C:34](=[O:37])[C:25]([CH3:30])([CH3:26])[CH3:24])[CH:15]([CH3:23])[CH3:16])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1cccc2c1ccn2-c1ccccc1C#N
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C(=O)OC(OC(=O)C(C)(C)C)C(C)C)n1Cc1cccc2c1ccn2-c1ccccc1C#N

Procedure:
A mixture containing 2-butyl-4-chloro-1-[[1-(2-cyanophenyl)-1H-indol-4-yl]methyl]-1H-imidazole-5-carboxylic acid (550 mg, 1.27 mmol, prepared as described in part C of Example 9), the title A compound (979 mg, 5.08 mmol), sodium iodide (381 mg, 2.54 mmol) and cesium carbonate (1.86 g, 5.72 mmol) in 2.5 mL of dimethylformamide was heated at 60° C. for 7 hours in a stoppered flask. Upon cooling the reaction mixture was diluted with 110 mL of ethyl acetate and filtered. The organic extract was rinsed with three 15 mL portions of pH 4 buffer, 20 mL of 1:1, water:brine and 30 mL of brine, then dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 1.3 g of crude product. Chromatography on 75 g of silica gel eluted with 4:1, hexanes:ethyl acetate yielded 567 mg of the title B compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](C2C=C3C(C(C4C=CC5C(=CC=CC=5)C=4)=NN3S(C3C(C)=CC(C)=CC=3C)(=O)=O)=CC=2)=[CH:11][C:10]=1[O:46][CH3:47])C1C=CC=CC=1.C(OC1C=CC([C:62]2[CH:70]=[C:69]3[C:65]([C:66]([C:71]4[CH:80]=[CH:79][C:78]5[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=5)[CH:72]=4)=[N:67][NH:68]3)=[CH:64][CH:63]=2)=CC=1OC)C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:72]1[C:73]2[C:78](=[CH:77][CH:76]=[CH:75][CH:74]=2)[CH:79]=[CH:80][C:71]=1[C:66]1[C:65]2[C:69](=[CH:70][CH:62]=[CH:63][CH:64]=2)[N:68]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:46][CH3:47])[CH:11]=2)[N:67]=1
Reactant: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)ccc1OCc1ccccc1
Reactant: COc1cc(-c2ccc3c(-c4ccc5ccccc5c4)n[nH]c3c2)ccc1OCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(-n2nc(-c3ccc4ccccc4c3)c3ccccc32)ccc1O

Procedure:
6-(4-Benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole was converted to 6-(4-benzyloxy-3-methoxy-phenyl)-3-naphthalen-2-yl-1H-indazole as described in Example 1(a), step (ix). Rf sm 0.40, p 0.17 (ethyl acetate-hexane 3:7); 1H NMR (CDCl3) δ 8.40 (s, 1H), 8.12 (d, 1H, J=8.5 Hz), 8.10 (dd, 1H, J=1.6, 8.4 Hz), 7.93 (d, 1H, J=8.3 Hz), 7.88 (m, 2H), 7.61 (m, 1H) 7.56 (s, 1H), 7.43 (m, 5H), 7.30 (m 3H), 7.15 (d, 1H, J=2.0 Hz), 7.08 (dd, 1H, J=2.1, 8.3 Hz), 6.91 (d, 1H, J=8.3 Hz), 5.16 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:20]=[C:19](I)[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>C(NCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:20]=[C:19]([C:27]#[C:26][CH2:25][OH:28])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-7-ethyl-2-iodo4-oxo4,7-dihydro-thieno[2,3-b]pyridine-5-carboxamide (Example No. 12) (0.267 g) in diethylamine (14 mL) is added copper iodide (0.032 g) and Pd(PPh3)2Cl2 (0.009 g) followed by addition of propargyl alcohol (39 mL). The reaction is stirred at rt for 18 h. The diethylamine is removed in vacuo, and the resulting residue is partitioned between H2O (25 mL) and CH2Cl2 (25 mL). The organic layer is removed, and the aqueous layer is extracted with CH2Cl2 (3×25 mL). The combined organic layers are dried with MgSO4, filtered, and concentrated in vacuo. The resulting orange solid is purified by column chromatography (CH2Cl2:CH3OH, 98:2). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.158 g (70%) of the title compound as a yellow, crystalline solid.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:21](O)=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCC1CCCCC1
Yield: 42.9 %

Procedure:
In 20 ml of tetrahydrofuran was dissolved 10 ml of a 65% toluene solution of sodium dihydrobis-(2-methoxyethoxy)-aluminate. To the solution was added dropwise 20 ml of tetrahydrofuran solution and 1.0 g of N-(cyclohexylmethoxycarbonyl)-tyrosine while stirring and cooling with ice. The mixture was stirred at room temperature for two hours. After addition of 5% hydrochloric acid, the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was crystallized from ethyl acetate-petroleum ether to give 410 mg of N-(cyclohexylmethoxycarbonyl)-tyrosinol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[NH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1>O1CCOCC1>[S:16]1[CH2:17][CH2:18][N:13]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([Cl:12])[N:3]=2)[CH2:14][CH2:15]1
Reactant: Clc1cc2ccccc2c(Cl)n1
Reactant: C1CSCCN1
Solvent: C1COCCO1
Product: Clc1cc2ccccc2c(N2CCSCC2)n1

Procedure:
A mixture of 19.8 gm (0.1 mol) of 1,3-dichloro-isoquinoline [prepared according to S. Gabriel, Berichte 19, 1655 (1886)], 25.8 gm (0.25 mol) of thiomorpholine and 100 ml of dry dioxane was refluxed for 7 hours. Thereafter, the precipitated thiomorpholine hydrochloride was suction-filtered off, the filtrate was evaporated and water was added to the residue. The reaction product was suction-filtered off, dried and recrystallized from ethyl acetate, yielding 18.4 gm (69.5% of theory) of the desired compound, m.p. 133°C. In analogous manner 1-(1-oxido-thiomorpholino)-3-chloro-isoquinoline, m.p. 167°-168°C (from ethyl acetate), was prepared from 1,3-dichloro-isoquinoline and 1-oxido-thiomorpholine.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:26]>>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2])=[CH:9][CH:10]=1
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2F)cc1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2F)cc1
Yield: 49 %

Procedure:
Prepared in analogy to example 3 from N-[4-(2,4-difluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=49%. Colorless solid. MS: m/e=321.1 (M++H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[CH2:29]([O:36][C:37]([C@@H:39]([NH:45]C(OC(C)(C)C)=O)[CH2:40][CH2:41][C:42](O)=[O:43])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl>ClCCl.C(N(CC)CC)C>[NH2:45][C@H:39]([C:37]([O:36][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:38])[CH2:40][CH2:41][C:42]([NH:28][CH2:27][CH2:26][O:25][CH2:24][C:7]1[NH:8][C:9]([CH3:23])=[C:10]([C:19]([O:21][CH3:22])=[O:20])[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:6]=1[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:43]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(COCCNC(=O)CC[C@H](N)C(=O)OCc2ccccc2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Yield: 17.2 %

Procedure:
The title compound (0.29 g) was prepared as an oil by the reaction of amlodipine (1.1 g), (S)-4-benzyloxycarbonyl-4-t-butoxycarbonylaminobutanoic acid (1.0 g) (commercially available), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.57 g), 1-hydroxybenzotriazole (0.40 g) and triethylamine (0.30 g) according to method of part (a) of Example 5 followed by treatment of the resulting intermediate in dichloromethane with gaseous hydrogen chloride according to the method of part (b).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:33]1[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:36]=[C:35]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:34]=1>>[C:43]([C:35]1[CH:34]=[C:33](/[C:27](/[Si:28]([CH3:29])([CH3:30])[CH3:31])=[CH:26]/[C:23]2[CH:22]=[CH:21][C:20]([CH2:19][OH:18])=[CH:25][CH:24]=2)[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:36]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)cc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)c1cc(/C(=C/c2ccc(CO)cc2)[Si](C)(C)C)cc(C(C)(C)C)c1

Procedure:
Following General Procedure A, 4-[(trimethylsilyl)ethynyl]benzyl tert-butyldiphenylsilyl ether and 1-bromo-3,5-Di-tert-butylbenzene (which can be prepared by the procedure described in Komen and Bickel Synth. Commun, 1996, 26, 1693-1698) were coupled to give the title compound (Compound 32). PNMR (300 MHz, CDCl3) δ7.40 (s, 4H), 7.33 (s, 2H), 7.08 (s, 1H), 7.07(s, 1H), 4.78 (d, J=5.9 Hz, 1H), 1.41 (s, 18H), 0.00 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[CH:23]1[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:25]1[CH2:26][CH2:27][CH2:28][CH:23]([C:15]2[N:14]([CH2:13][CH2:12][N:3]3[C:4](=[O:11])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc3ccccc3n2CCN2C(=O)c3ccccc3C2=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2C(=O)N1CCn1c(C2CCCNC2)nc2ccccc21

Procedure:
tert-Butyl 3-(1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (129A) (4.36 mmoles max, crude mixture) was added to a 20 mL scintillation vial equipped for stirring. CH2Cl2 (3 mL) and trifluoroacetic acid (1 mL) were then added and the resultant solution was allowed to stir at room temperature for 72 hrs. The reaction was concentrated and dried in-vacuo affording 2-(2-(2-(piperidin-3-yl)-1H-benzo[d]imidazol-1-yl)ethyl)isoindoline-1,3-dione (129B) as a mixture that was used without further purification. ESI-MS: m/z 375.3 (M+H)+.
Reaction SMILES: CS([C:5]1[N:6]=[N:7][CH:8]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:10]=1)(=O)=O.[NH3:17]>C1COCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[N:16][C:11]=1[C:9]1[N:10]=[C:5]([NH2:17])[N:6]=[N:7][CH:8]=1
Reactant: CS(=O)(=O)c1nncc(-c2ncccn2)n1
Reactant: N
Solvent: C1CCOC1
Product: Nc1nncc(-c2ncccn2)n1
Yield: 23 %

Procedure:
5-(Pyrimidin-2-yl)-1,2,4-triazin-3-amine (1.0 g, 23%) was prepared from 3-(methylsulfonyl)-5-(pyrimidin-2-yl)-1,2,4-triazine (5.0 g, crude) and 0.5 M ammonia in THF (20 mL) according to the general procedure of Preparation 2.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[C:21]([CH3:28])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:6]=1>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[NH2:25][C:23]1[CH:22]=[C:21]([CH3:28])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:6]=2)=[C:2]([Cl:1])[CH:24]=1
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1Oc1ccc(O)c(COc2ccc(F)cc2)c1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(N)cc(Cl)c1Oc1ccc(O)c(COc2ccc(F)cc2)c1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a warm (100° C.) solution of 4-(2-chloro-6-methyl-4-nitro-phenoxy)-2-(4-fluorophenoxymethyl)-phenol (100 mg) in glacial acetic acid (2.5 mL) was added zinc dust (243 mg) and heating was continued for 30 min. The reaction mixture was cooled, diluted with ethyl acetate and filtered through Celite®. The filtrate was washed with 1M aqueous sodium bicarbonate, dried over sodium sulfate, concentrated in vacuo and flashed chromatographed (30% ethyl acetate/hexanes) to afford 4-(4-amino-2-chloro-6-methyl-phenoxy)-2-(4-fluoro-phenoxymethyl)-phenol (90 mg) as a tan solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:24][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([CH2:14][CH:9]3[CH:10]([CH3:13])[CH2:11][CH2:12][NH:8]3)=[CH:16][NH:17]2)=[CH:22][CH:21]=1
Reactant: CC1CCN(C(=O)OC(C)(C)C)C1Cc1c[nH]c2cc(F)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCNC1Cc1c[nH]c2cc(F)ccc12
Reaction time: 2 h
Yield: 107.6 %

Procedure:
To solution containing 66 (0.89 g, 0.0024 mol) in DCM (20 mL) at 0° C. was added TFA (4 mL). After 2 h, TLC analysis revealed complete consumption of 66 [10% MeOH/DCM, Rf(66)=0.7, Rf(67)=0.3]. The reaction mixture was concentrated in vacuo, diluted with DCM, washed with aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 0.6 g (86%) of 67 which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ9.0 (br s, 1H), 7.6-7.35 (m, 1H), 7.1-6.7 (m, 3H), 4.2 (br m, 1H), 3.2-2.5 (m, 5H), 2.1-1.2 (m, 3H), 1.05 (d, J=6.74 Hz, 3H) ppm.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>C(#N)C>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:6]=2)=[CH:28][CH:27]=1
Reactant: NCc1ccc(F)cc1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)cc1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 4-fluorobenzylamine and acetonitrile essentially as described above in example 18 except that the column is eluted using a solvent gradient of 40% ethyl acetate in heptane, to 100% ethyl acetate. Purity by LC/MS (APCI)=100%, [M+H]+=369.
Reaction SMILES: [CH3:1][C:2]([C:6]1([OH:21])[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)([CH3:5])[CH:3]=[O:4].CC(C)=[O:24].Cl.O.[Mn]([O-])(=O)(=O)=O.[K+]>>[CH2:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:6]([C:2]([CH3:1])([CH3:5])[C:3]([OH:24])=[O:4])([OH:21])[CH2:7]1)=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)=O
Reactant: CC(C)(C=O)C1(O)CCN(C(=O)OCc2ccccc2)C1
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(C(=O)O)C1(O)CCN(C(=O)OCc2ccccc2)C1
Temperature: 15 °C
Reaction time: 6 h

Procedure:
Benzyl 3-(1,1-dimethyl-2-oxoethyl)-3-hydroxypyrrolidine-1-carboxylate (12.70 g, 0.04359 mol) was dissolved in acetone (179.5 mL, 2.444 mol) and cooled to 15° C. and 1.0 M of hydrogen chloride in water (65.39 mL, 0.06539 mol) was added dropwise. After addition of the HCl was complete, a solution of potassium permanganate (11.0 g, 0.0697 mol) in acetone (493.6 mL, 6.722 mol) was added dropwise. The reaction mixture was stirred at room temperature for 6 h, filtered and the filter cake was washed with acetone. The filtrate was evaporated, in vacuo, diluted with methylene chloride, dried, filtered and the solvent was evaporated, in vacuo, to provide a crude product which was used directly in next step. LCMS (M+H) 308.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:13][O:12]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1>CCO.O>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:12])[CH2:13][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Reactant: CC(C)(C)OC(=O)NCCCC1CO1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC(O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 37.7 %

Procedure:
A solution of ((rac)-3-oxiranyl-propyl)-carbamic acid tert-butyl ester (1.08 g, 5.34 mmol) and 6-amino-4H-benzo[1,4]thiazin-3-one (1.01 g, 5.61 mmol) in 9:1 EtOH/H2O (20 mL) was heated at 70° C. overnight. After cooling the mixture was concentrated in vacuo and chromatographed on SiO2 (DCM-MeOH—NH4OH: 1000:50:4) to afford the title intermediate as beige foam (767 mg, 38% yield).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:35][O:36][CH2:37][CH3:38])[N:23]([CH2:24][C:25]([NH:28][C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])([CH3:27])[CH3:26])[C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[CH:14][C:13]=2[N:12]=1.C(N(CC)CC)C>ClCCl>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:35][O:36][CH2:37][CH3:38])[N:23]([CH2:24][C:25]([NH:28][C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])([CH3:26])[CH3:27])[C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46][S:2]([CH3:1])(=[O:5])=[O:3])=[CH:14][C:13]=2[N:12]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNS(C)(=O)=O)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
Methanesulfonic anhydride (0.34 g, 1.93 mmol) was added to a stirred solution of N-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea (prepared as described in Parts A-H of Example 369, 10.9 g, 1.75 mmol) and triethylamine (0.35 mL, 3.5 mmol) in dichloromethane (50 mL) at 0° C. After approximately 30 minutes, the solution was allowed to warm to room temperature and was stirred overnight. The following morning, the solution was cooled to 0° C. and additional methanesulfonic anhydride (0.13 g) was added. After 30 minutes, the solution was allowed to warm to room temperature. After 2 hours, the solution was transferred to a separatory funnel and washed with water (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, elution with 10% methanol in dichloromethane) followed purification by chromatography on a HORIZON HPFC system (an automated, modular high-performance flash purification product available from Biotage, Inc, Charlottesville, Va., USA) (silica gel, gradient elution with 0-40% CMA in chloroform where CMA is a solution of 80:18:2 chloroform/methanol/concentrated ammonium hydroxide) to yield 0.31 g of N-(6-{[4-amino-2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)methanesulfonamide as an off white solid, mp 190-194° C.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:20][C:21]1([CH3:26])[O:25][CH2:24][CH2:23][O:22]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:17][CH2:18][CH3:19].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>>[CH3:27][C:2]([CH3:1])([CH2:20][C:21]1([CH3:26])[O:25][CH2:24][CH2:23][O:22]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-:36])=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:17][CH2:18][CH3:19]
Reactant: CCCc1nc2cnc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CC(C)(C)CC1(C)OCCO1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-propyl-1H-imidazo[4,5-c]quinoline (3.10 g, 8.44 mmol) by reaction with m-CPBA (3.70 g) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-5-oxido-2-propyl-1H-imidazo[4,5-c]quinoline followed by reaction with p-toluenesulfonyl chloride (2.80 g, 14.7 mmol) and ammonium hydroxide solution (100 mL) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as off-white needles after recrystallization from aqueous methanol, mp 186-188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=2)=[O:16])=[CH:13][CH:12]=1
Reactant: Nc1cccc(C=O)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=Cc1cccc(NC(=O)c2ccc(Cl)cc2)c1
Yield: 129 %

Procedure:
to a solution of 242 mg of 3-aminobenzaldehyde (2 mmoles) and 250 μl of 4-chlorobenzoyl chloride (2 mmoles) in 5 ml of DMF is added 700 μl of DIEA (4 mmoles). The reaction is irradiated in under microwaves at 110° C. for 10 minutes. The precipitate formed is filtrated and washed with methanol. 670 mg of 4-Chloro-N-(3-formyl-phenyl)-benzamide are isolated as a white solid (yield=85%). Analytical LC/MS method A: ([M+H]+): 260