Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH2:43][CH:42]([C:46]([NH2:48])=[O:47])[CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH2:43][CH:42]([C:46]([NH2:48])=[O:47])[CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Reactant: NC(=O)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1CCCC(C(N)=O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and piperidine-3-carboxamide (49 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (45 mg, yield 72%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[CH3:25][O:26][C:27]1[N:32]=[C:31]2[S:33][C:34]([NH2:36])=[N:35][C:30]2=[CH:29][CH:28]=1>S(Cl)(Cl)=O.N1C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:36][C:34]2[S:33][C:31]3[C:30]([N:35]=2)=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[N:32]=3)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc2nc(N)sc2n1
Reactant: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc([N+](=O)[O-])cc3)sc2n1
Reaction time: 5 h

Procedure:
The title B compound, 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (7.5 g, 28.5 mmol) is dissolved in 25 mL of thionyl chloride and a drop of DMF and the mixture stirred at RT for 5-6 h. The excess of thionyl chloride is removed under reduced pressure. The residue is then taken up in DCM and added dropwise to a solution of the title E compound in Example 1, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (5.2 g, 28.5 mmol) in 25 mL of pyridine. The reaction mixture is stirred for 5 h before being evaporated to remove the pyridine. The residue is partitioned between ethyl acetate and brine, extracted with ethyl acetate. The combined organic layers are washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and then reduced to an orange-brown solid. This is then vacuum dried to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-(4-nitro-phenyl)-propionamide as a foam: 1H NMR (400 MHz, CDCl3) δ 1.0-1.1 (m, 2H), 1.4-1.8 (m, 5H), 1.8-1.9 (m, 2H), 2.1-2.25 (m, 2H), 3.6 (t, 1H, J=7.8), 4.01 (s, 3H), 6.8 (d, 1H, J=8.8), 7.4 (d, 2H, J=8.6), 7.8 (d, 1H, J=8.8 Hz), 8.19 (d, 2H, J=8.6 Hz), 9.3 (s, 1H); LC/MS 427 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:14]([CH:15]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[O:16][CH3:17])=[C:13]([Cl:23])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[C:14]([CH:15]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)[O:16][CH3:17])=[C:13]([Cl:23])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(c1ccco1)c1c(Cl)ccc(C(=O)OC(C)(C)C)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(c1ccco1)c1c(Cl)ccc(C(=O)O)c1Cl

Procedure:
2.3 g (6.4 mmol) of tert-butyl 2,4-dichloro-3-((2-furyl)(methoxymethyl))benzoate in 50 ml of methanol and 15 ml of water are heated under reflux with 0.7 g (16.1 mmol) of sodium hydroxide for 4 h. 5.0 ml of a 10% strength aqueous sodium hydroxide solution are added and the mixture is heated for a further 3 h. After the reaction mixture has been concentrated under reduced pressure, 50 ml of water are added and the reaction mixture is extracted with dichloromethane. The aqueous phase is acidified using 10% strength aqueous hydrochloric acid and the product is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and freed from the solvent under reduced pressure. Yield 1.8 g.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:18])C=1>C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:18])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
A mixture of isopropylpyridine (2.1 g, 17.75 mmol) and m-CPBA (5.0 g, 1.3 eq.) in CH2Cl2 was stirred overnight at room temperature. Then, the reaction mixture was diluted with CH2Cl2 (twice the volume) and successively washed with aqueous sodium bicarbonate (twice) and brine, dried (Na2SO4) and evaporated to give 2.0 g (85%) of the title compound 104.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH:13]=O)[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]1([NH2:18])[CH2:17][CH2:16]1.[BH4-].[Na+].O>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([O:5][C:6]([N:8]([CH:9]1[CH2:11][CH2:10]1)[CH2:12][CH2:13][NH:18][CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: CC(C)N(CC=O)C(=O)OC(C)(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CC(C)NCCN(C(=O)OC(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.2 %

Procedure:
3.9 mL (13 mmol) of titanium isopropoxide and 2 g (10 mmol) of (tert-butoxycarbonyl-isopropyl-amino)-acetaldehyde (prepared according to the method described by Kato, Shiro et al., J. Chem. Soc. Perkin Trans. 1, 1997, 21, 3219-26) are added to a solution of 1.71 g (30 mmol) of cyclopropylamine in 15 mL of anhydrous methanol. The solution is stirred for 5 hours at room temperature then 454 mg (12 mmol) of sodium borohydride is added. Stirring is continued for a further 2 hours then 2 mL of water is added. The reaction mixture is filtered then the solvents are evaporated. The residue is purified by chromatography on silica (eluent dichloromethane/methanol 98/2 then 95/5) to give 852 mg (35%) of N-tert-butoxycarbonyl-N-cyclopropyl-N′-isopropyl-ethane-1,2-diamine in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:12][CH3:13])=[N:9][C:10]=2I)[CH:7]=1.C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:12][CH3:13])=[N:9][C:10]=2[Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=1
Reactant: CSc1nc(I)c2ccc(F)cn12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc(SC)n2cc(F)ccc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
In a round-bottomed flask, 6-fluoro-1-iodo-3-methylsulfanyl-imidazo[1,5-a]pyridine (109 mg, 0.35 mmol) was dissolved in THF (3 ml). The light brown solution was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.21 ml, 0.42 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 20 min then tributylchlorostannane (0.11 ml, 0.40 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 2 h then quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 6-fluoro-3-methylsulfanyl-1-tributylstannanyl-imidazo[1,5-a]pyridine as a brown oil which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].CN.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C[CH2:50][N:51](C(C)C)C(C)C>CN(C=O)C>[CH3:50][NH:51][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]([F:28])([F:27])[F:29])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14]
Reactant: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC)ccc21

Procedure:
1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (50.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), methylamine (2.0 M solution in THF, 1 mL), DPPA (82.0 mg), and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 437; and 1H NMR (CD3OD, 400 MHz): δ 7.93 (1H, d), 7.73-7.70 (2H, m), 7.64-7.63 (1H, d), 7.40-7.38 (1H, m), 7.25-7.22 (1H, m), 4.25-4.23 (2H, q), 2.95 (3H, s), 1.41-1.38 (3H, t), 2 —NH proton signals were not observed.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[CH2:3][CH2:4][C:5]#[N:6].C(N(C(C)C)CC)(C)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]([CH3:9])([CH2:7][O:8][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:3][CH2:4][C:5]#[N:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CO)CCC#N
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CCC#N)CO[Si](C)(C)C(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of 16.13 g (0.127 mmol) of 4,4-dimethyl-5-hydroxyvaleronitrile in 250 mL of dry CH2Cl2 was added, at 20° C., in 2 min., 24.2 mL (0.139 mmol; 1.09 eq) of diisopropylethylamine, followed after 5 min. by 25.0 g (0.165 mmol; 1.3 eq) of solid t-butyldimethylsilyl chloride, all at once. Then, 1.55 g (0.0127 mmol; 0.1 eq) of 4-dimethylaminopyridine was added and the whole was stirred at 20° C. during 18h. After removing the solvent under vacuum (aspirator) the brown residue was taken up in H2O, followed by ethyl ether. The layers were separated and the aqueous one extracted three times with 200 mL of ether. The combined organic layers were back extracted with water (100 mL), HCl 1.2N (100 mL), 5% KHCO3 (2×100 mL), dried over Na2SO4 and concentrated under vacuum to give a faint yellow oil. Distillation at 94°-97° C. (0.7 mm) gave 21 g (69%) of the title compound. TLC:(Silica),Rf 0.59(CH2Cl2), detection with molybdophosphoric acid blue on yellow.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[C:12]([C:16]1[CH:46]=[CH:45][C:19]([C:20]([C:22]2[C:23]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[C:24]3[C:29](=[CH:30][C:31]=2[CH:32]([CH3:34])[CH3:33])[O:28][C:27]([CH3:36])([CH3:35])[CH2:26][C:25]3=[O:37])=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CO>O1CCCC1>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[C:23]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)=[C:24]3[C:29](=[CH:30][C:31]=2[CH:32]([CH3:34])[CH3:33])[O:28][C:27]([CH3:35])([CH3:36])[CH2:26][C@@H:25]3[OH:37])=[O:21])=[CH:45][CH:46]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(C(C)(C)C)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
78 μl (540 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 2.46 mg (20 μmol) of (1R,2S)-1-aminoindan-2-ol in 2 ml of tetrahydrofuran. The mixture is then cooled to 0° C., and a solution of 52 mg (110 μmol) of 6-(4-tert-butylbenzoyl)-5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 29A) in 3 ml of tetrahydrofuran are slowly added dropwise. The mixture is then allowed to thaw slowly and stirred at room temperature overnight. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative HPLC (method 1) and subsequent chiral HPLC (method 2) gives the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[OH:11].Br[CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[C:17]1([CH2:16][CH2:15][CH2:14][CH2:13][O:11][C:4]2[CH:5]=[CH:6][C:7]([CH:9]=[O:10])=[CH:8][C:3]=2[O:2][CH3:1])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: BrCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COc1cc(C=O)ccc1OCCCCc1ccccc1
Yield: 37.5 %

Procedure:
A mixture of 860 mg of vaniline, 1.00 g of 4-bromobutylbenzene, 1.00 g of potassium carbonate and 8 ml of 2-butanone was heated under reflux for 3 hours. The reaction mixture was poured into water and the product was extracted with ether. The ethereal layer was washed with water, dried and concentrated. The obtained residue was applied to silica gel column chromatography and eluted with toluene to obtain 500 mg of 4-(4-phenylbutoxy)-3-methoxybenzaldehyde.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:22]([CH3:23])[CH2:21][CH2:20][C@:16]45[C:17]=2[C:18]=1[O:19][C@H:15]4[C@@H:14]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[CH:13]=[CH:12][C@@H:11]35)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:22]([CH3:23])[CH2:21][CH2:20][C@:16]45[C:17]=2[C:18]=1[O:19][CH:15]4[C@@H:14]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:32])[CH3:31])[CH2:13][CH2:12][C@@H:11]35)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCO[C@H]1C=C[C@H]2[C@H]3Cc4ccc(OC(C)=O)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: [Pd]
Solvent: CO
Product: CC(=O)OCCCCO[C@H]1CC[C@H]2[C@H]3Cc4ccc(OC(C)=O)c5c4[C@@]2(CCN3C)C1O5
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6α-((4-Acetyloxy-butyl)-oxy)-4,5α-epoxy-17-methyl-morphinan-7-en-3-ol acetate (0.288 g, 0.63 mmol) in MeOH (30 ml) mixed with 10% Pd on 0.2 g) and then agitated for 1 hour at RT under H2 (1 bar over pressure). The catalyst is removed by filtering through a filter compound and the filtrate is concentrated by rotary evaporation. The residue obtained is purified by flash chromatography (20 g silica gel; mobile phase: CH2Cl2 /MeOH=9/1). The product is dissolved in glacial acetic acid and lyophilised.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].C(N(CC)CC)C.Cl[CH2:32][CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36].N12CCCN=C1CCCCC2>ClCCl.O>[O:36]=[S:35]1(=[O:37])[CH2:34][CH2:33][CH2:32][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23]
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)CCCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: O
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCN1CCCS1(=O)=O
Reaction time: 2 h
Yield: 43.3 %

Procedure:
Under a nitrogen atmosphere, 1-(4-aminobutyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.6 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (0.33 mL, 2.4 mmol). 3-Chloropropylsulfonyl chloride (0.19 mL, 1.6 mmol) was added dropwise and the reaction was stirred for 2 hours. The solvent was removed in vacuo. The residue was dissolved in N,N-dimethylformamide (5 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.48 mL, 3.2 mmol) was added. The reaction was stirred for 72 hours and then poured into water and extracted with dichloromethane. The organic layer was washed with water followed by brine; dried (Na2SO4); decanted and evaporated to yield crude product as a brown oil. Purification involved flash column chromatography (silica gel, gradient elution with methanol/dichloromethane 100:0 to 94:6) followed by recrystallization from acetonitrile to provide 289 mg of 1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a yellow crystalline solid, m.p. 156.4-157.7° C.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27]C1>>[O:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:3]([C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:6]=2)=[O:4])[CH2:27]1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NC2CCOC2)on1
Yield: 12.7 %

Procedure:
As described for example 14e, 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.32 mmol) was converted, using 4-aminotetrahydropyran (33 mg, 0.38 mmol) instead of isopropyl amine, to the title compound (15 mg, 13%) which was obtained as a white solid after purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:4). MS: m/e=371.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1.[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1F>C1COCC1.CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[O:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OCc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 1.4 g, 33.5 mmol) was suspended in anhydrous THF (50 ml) under nitrogen and the resulting mixture is cooled to 0° C. To above suspension was added dropwisely (3-Fluoro-phenyl)-methanol (2.90 ml, 27 mmol), followed by a solution of 2-chloro-1-fluoro-4-nitro-benzene (4.2 g, 24 mmol) in dry DMF (20 ml). The reaction mixture was then stirred at room temperature for another 4 hours. The reaction mixture concentrated under vacuum to about 40 mL, and was poured into 200 ml of ice:water. The resultant solid was isolated by filtration, washed with water (50 ml), and air dried to yield a yellow solid, 2-Chloro-1-(3-fluoro-benzyloxy)-4-nitro-benzene (5.8 g). The solid was suspended in MeOH (50 ml) and treated wet 5% Pt/C (Degussa type, Aldrich, 1.5 g). The flask is flushed with hydrogen gas from a balloon and the reaction mixture was stirred under hydrogen balloon for 2 hours. The reaction mixture was filtered through a Celite plug and the solvent is removed under reduced pressure to yield 5.2 g of the desired product.
Reaction SMILES: S1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C@@H:27]([CH3:31])[CH2:28][O:29][CH3:30])[CH:25]=3)[C:14]([NH:16][C:17]3[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=3)=[O:15])=[CH:9][C:4]=2[CH:3]=[CH:2]1.O[O:33][S:34]([O-:36])=O.[K+]>CO.O>[O:33]=[S:34]1(=[O:36])[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([CH:23]=[C:24]([O:26][C@@H:27]([CH3:31])[CH2:28][O:29][CH3:30])[CH:25]=3)[C:14]([NH:16][C:17]3[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=3)=[O:15])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=S([O-])OO
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3sccc3c2)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)C=CS3(=O)=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.7 %

Procedure:
To a solution of 3-(1-benzothien-5-yloxy)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (178 mg, 0.41 mmol) in methanol (3 mL) at 0° C. was added dropwise a solution of oxone (752 mg, 1.22 mmol) in water (3 mL). The resultant cloudy slurry was allowed to warm to RT and stir for 16 hours. Water (20 mL) was added and the mixture extracted with DCM (3×20 mL). The combined extracts were dried (MgSO4), filtered and evaporated. The material was chromatographed on silica, eluting with 0-3% methanol in DCM, to give the desired compound as yellow oil (113 mg). m/z 470 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([O:13][CH:14]([CH3:16])[CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:18][S:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30]CS([O-])(=O)=O)=[CH:25][CH:24]=1)(=[O:21])=[O:20]>>[CH3:1][O:2][C:3](=[O:17])[CH:4]([O:13][CH:14]([CH3:15])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:30][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([O:22][S:19]([CH3:18])(=[O:20])=[O:21])=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Oc1ccc(CCCS(=O)(=O)[O-])cc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)OC(C)C
Product: COC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OC(C)C

Procedure:
2-Isopropoxy-3-[4-(2-{4-methylsulfonyloxyphenyl}ethoxy)phenyl]propanoic acid methyl ester was synthesized from 3-(4-hydroxyphenyl)-2-isopropoxypropanoic acid methyl ester and 2-(4-methanesulfonyloxyphenyl)ethylmethanesulfonate (described in Example 1b) using the same method as in Example 58e.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:17]([CH3:24])([CH3:23])[C:18](OCC)=[O:19]>CC(C)=O>[Br:9][C:4]1[CH:5]=[CH:6][C:7]2[O:8][C:17]([CH3:24])([CH3:23])[C:18](=[O:19])[NH:1][C:2]=2[N:3]=1
Reactant: Nc1nc(Br)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)Oc2ccc(Br)nc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a suspension of 2-amino-6-bromopyridin-3-ol (250 mg, 1.32 mmol) and K2CO3 in acetone (5 mL) was added ethyl 2-bromoisobutyrate (0.29 ml, 1.98 mmol) and the reaction was stirred for 1 hour at room temperature and overnight at reflux. The acetone was removed, and to the residue was added dichloromethane and water. The layers were separated and the aqueous was extracted with dichloromethane (1x). The organic layer was dried (MgSO4), filtered, and concentrated to afford 6-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one 7.27 (300 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C9H10BrN2O2: 257.0; found: 257.1.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:45]1[C:46]([OH:54])=[CH:47][C:48]3[O:52][CH2:51][CH2:50][C:49]=3[CH:53]=1)[C:31](=[O:44])[N:32]2[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>>[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30]([C:45]1[C:46]([OH:54])=[CH:47][C:48]3[O:52][CH2:51][CH2:50][C:49]=3[CH:53]=1)([CH2:5][OH:16])[C:31](=[O:44])[N:32]2[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2c(Br)cccc2N1Cc1ccccn1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1N(Cc2ccccn2)c2cccc(Br)c2C1(CO)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-(pyridin-2-ylmethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (34%): MS (ES+) m/z 468.4 (M+1).