Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([S:34]([NH2:37])(=[O:36])=[O:35])[CH2:8][C@@H:9]1[CH2:13][C@@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:11][C@@H:10]1[OH:33])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[C@@H:24]1([NH:23][C:22]2[C:17]3[CH:16]=[CH:15][N:14]([C@@H:12]4[CH2:13][C@@H:9]([CH2:8][NH:7][S:34]([NH2:37])(=[O:36])=[O:35])[C@@H:10]([OH:33])[CH2:11]4)[C:18]=3[N:19]=[CH:20][N:21]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N(C[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O)S(N)(=O)=O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)NC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Reaction time: 0.25 h

Procedure:
tert-Butyl(aminosulfonyl)[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]carbamate (345 mg, 0.000636 mol) was dissolved in 2:1 methylene chloride:trifluoroacetic acid (20 mL: 10 mL) and left to stand for 15 minutes at room temperature. The mixture was diluted with toluene (30 mL) and evaporated to dryness. The residue was then re-subjected to the same conditions and azeotroped with toluene after completion. The residue was purified by silica gel chromatography, eluting with 5 to 10% Methanol in dichloromethane, to yield the product, 135 mg (48%). 1H-NMR (400 MHz, MeOD) δ 8.16 (s, 1H), 7.19 (m, 5H), 6.62 (d, J=3.6 Hz, 1H), 5.85 (t, J=7.8 Hz, 1H) 5.43 (ddd, J=4.6 Hz, 8.5 Hz, 17.8 Hz, 1H), 4.46 (t, J=3.6 Hz, 1H), 3.15 (dd, J=7.1 Hz, 12.9 Hz, 1H), 3.05 (ddd, J=3.3 Hz, 8.7 Hz, 15.4 Hz, 1H), 2.91 (m, 1H), 2.63 (m, 1H), 2.33 (ddd, J=1.5 Hz, 8.0 Hz, 13.8 Hz, 1H), 2.20 (m, 2H), 2.02 (m, 2H). LC/MS: Rt=1.45 min, ES+ 443 (AA standard).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:7][CH:8]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:18])[CH3:19])[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1)=[O:30]
Reactant: CCOC(=O)C(Cc1cccc(CO)c1)OC(C)C
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Product: CC(C)OC(Cc1cccc(COC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)O

Procedure:
Using ethyl 3-[3-(hydroxymethyl)phenyl]-2-isopropoxypropanoate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:12][O:11][C:10](=[O:13])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[N+:16]([O-])([OH:18])=[O:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:12][O:11][C:10](=[O:13])[CH2:9]2)=[O:7])=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C1CC(C(=O)c2ccc(Cl)cc2)CO1
Reactant: O=[N+]([O-])O
Product: O=C1CC(C(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.37 g (15 mmol) of 4-(4-chlorobenzoyl)-tetrahydrofuran-2-one are added portion wise to 30 ml of nitric acid (100%) at -15° C. The temperature should not exceed -5° C. Stirring is continued for 30 minutes after all the compound has been added and the mixture is then poured out on 300 ml of ice water and the solid which has precipitated is separated by suction filtration and washed with water.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][C:34]([NH:37][C:38](=[O:40])[CH3:39])([CH3:36])[CH3:35])[C:31]([CH2:41][O:42][CH2:43][CH3:44])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][C:34]([NH:37][C:38](=[O:40])[CH3:39])([CH3:36])[CH3:35])[C:31]([CH2:41][O:42][CH2:43][CH3:44])=[N:30][C:25]=3[CH:26]=[N+:27]([O-:9])[C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(C)=O
Reaction time: 4 h
Yield: 100.5 %

Procedure:
mCPBA (60% pure, 1.70 g,) was added to a solution of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide (1.71 g, 3.83 mmol) in chloroform (100 mL). The reaction was stirred for 4 hours and then an additional 0.57 g of mCPBA was added. The reaction was stirred for 2 more hours and then quenched by adding aqueous 1% sodium carbonate. The layers were separated and the aqueous fraction was extracted with five portions of chloroform. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 1.78 g of crude N-[2-(7-benzyloxy-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide as an orange foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N+:18]([C:21]1[CH:35]=[CH:34][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:35][CH:34]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)CCCCCOc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CCCCCOc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a mixture of 4-nitrophenol (10.8 g), triethylamine (22 ml) in ethyl acetate (200 ml) at 0° C. was added 6-(4-nitrophenoxy)-hexanoyl chloride (20 g) dropwise, and the mixture was further stirred at room temperature for 16 hours. The reaction mixture was filtered to remove the salts, washed with 5% sodium bicarbonate, water and dried over anhydrous sodium sulphate. The solvent was distilled off under vacuum and the pure compound was precipitated by adding cold methanol. After filtration and drying, the compound was further recrystallized from a mixture of chloroform and methanol (1:1) to give pure 6-(4-nitrophenoxy)-hexanoic acid 4-nitrophenyl ester (15 grams) as white powder with a melting point of 73-76° C. The product was also characterized by 1H NMR (CDCl3) δ 1.60 (m, 2H, CH2), 1.85 (m, 6H, CH2X2), 2.70 (t, 2H, CH2), 4.10 (t, 2H, CH2), 6.95 (d, 2H, Ar), 7.30 (d, 2H, Ar), 8.25 (m, 4H, Ar).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[C:4]([C:8]([CH3:20])=[C:9]([N:11]([CH2:18][CH3:19])[CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:10]=1)[C:5]([OH:7])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:64][CH2:65][C:66]1[C:67](=[O:74])[NH:68][C:69]([CH3:73])=[CH:70][C:71]=1[CH3:72]>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:21])=[C:4]([C:8]([CH3:20])=[C:9]([N:11]([CH2:18][CH3:19])[CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:10]=1)[C:5]([NH:64][CH2:65][C:66]1[C:67](=[O:74])[NH:68][C:69]([CH3:73])=[CH:70][C:71]=1[CH3:72])=[O:7]
Reactant: CCN(c1cc(Br)c(F)c(C(=O)O)c1C)C1CCOCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cc(Br)c(F)c(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To a solution of 3-bromo-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzoic acid (200 mg, 0.56 mmol) in N,N-Dimethylformamide (2 ml) at room temperature and under nitrogen was added PyBOP (346.72 mg, 0.67 mmol) followed by N-ethyl-N-(propan-2-yl)propan-2-amine (145 μl, 0.83 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 104 mg, 0.61 mmol). After stirring for 1 hour at room temperature no starting material was observed by LCMS. EtOAc (20 ml) was added to the reaction mixture and this was then washed with deionized water (5 ml) followed by saturated NaHCO3 (aq) (3×5 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was then purified by FCC (5 g silica, Isolute cartridge, gradient of eluents; 100% DCM to 97:3 DCM:MeOH) to give 112 mg (41%) of 3-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzamide as a pale yellow solid. LC-MS 97%, 1.85 min (3 minute LC-MS method), m/z=494.0/496.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 11.66 (s, 1H), 7.23 (d, J=6.5 Hz, 1H), 5.95 (s, 1H), 4.65-4.43 (m, 2H), 3.93 (d, J=11.0 Hz, 2H), 3.38-3.22 (m, 2H), 2.97 (q, J=7.0 Hz, 2H), 2.91-2.79 (m, 1H), 2.37 (s, 3H), 2.24-2.11 (m, 6H), 1.72-1.53 (m, 4H), 0.83 (t, J=7.0 Hz, 3H).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:36][S:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46]([NH:49][C:50]1[CH:51]=[CH:52][CH:53]=[C:54]2[C:58]=1[NH:57][C:56]([C:59]([NH:61][CH2:62][CH2:63][S:64]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)=[CH:55]2)(=[O:48])=[O:47])(=[O:39])=[O:38]>ClCCl>[S:64]1[CH2:63][CH2:62][N:61]=[C:59]1[C:56]1[NH:57][C:58]2[C:54]([CH:55]=1)=[CH:53][CH:52]=[CH:51][C:50]=2[NH:49][S:46]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[S:37]([CH3:36])(=[O:39])=[O:38])(=[O:48])=[O:47]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1cccc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1cccc2cc(C3=NCCS3)[nH]c12
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
To a solution of triphenylphosphine oxide (4.27 g) in dichloromethane (20 mL) was slowly added trifluoromethanesulfonic anhydride (1.30 mL) at 0° C. The mixture was stirred for 10 min, and 7-{[2-(methylsulfonyl)phenylsulfonyl]amino}-N-[2-(tritylthio)ethyl]-1H-indole-2-carboxamide (1.78 g) was added. The reaction mixture was stirred at room temperature for 3 hr and concentrated. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.69 g, yield 63%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point 211-212° C.
Reaction SMILES: CO.C([C:5]1[N:6]([CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:7]2[C:16]3[CH:15]=[CH:14][C:13](C=CS(C)(=O)=O)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:23])[C:8]=2[N:24]=1)C>[Pd].C(O)C>[O:29]1[CH2:30][CH2:31][CH:26]([CH2:25][N:6]2[C:7]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=[C:9]([NH2:23])[C:8]=3[N:24]=[CH:5]2)[CH2:27][CH2:28]1
Reactant: CCc1nc2c(N)nc3cc(C=CS(C)(=O)=O)ccc3c2n1CC1CCOCC1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Nc1nc2ccccc2c2c1ncn2CC1CCOCC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (0.2 g), methanol (25 mL), ethanol (25 mL) and 2-ethyl-7-[2-(methylsulfonyl)ethenyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (315 mg, 0.76 mmol). The vessel was evacuated and charged with hydrogen gas (40 psi, 2.8×105 Pa). The reaction was shaken at 50° C. for approximately 18 hours and then cooled to ambient temperature. The reaction mixture was sequentially filtered, concentrated under reduced pressure, and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with CMA:chloroform gradient, 0-10% CMA over 1000 mL followed by 10-25% CMA over 1000 mL). A final recrystallization from acetonitrile provided 125 mg of 2-ethyl-7-[2-(methylsulfonyl)ethyl])-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white crystalline solid, mp 246.5-249.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[CH2:18](OS(C1C=CC(C)=CC=1)(=O)=O)[C@@H:19]1[O:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:21]1[CH2:20][C@@H:19]1[CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([F:14])([F:12])[F:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CC(=O)c1cc(S(=O)(=O)C(F)(F)F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(S(=O)(=O)C(F)(F)F)ccc1OC[C@H]1CO1

Procedure:
Preparation according to Preparation 23 using 1-{2-hydroxy-5-[(trifluoromethyl)sulfonyl]phenyl}ethanone (3.2 g, 11.9 mmol), (R)-glycidyltosylate (3.2 g, 14 mmol), K2CO3 (2.0 g, 14.3 mmol) and DMF (30 ml). Yield 2.2 g. MS m/z (rel. intensity, 70 eV) 324 (M+, 4), 277 (83), 255 (69), 253(67), 199 (bp).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:37]([O:41][C:42]([NH:44][C@H:45]([C:49]([OH:52])([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[C:37]([O:41][C:42](=[O:43])[NH:44][C@@H:45]([C:46]([N:13]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:47])[C:49]([OH:52])([CH3:50])[CH3:51])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)O
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)O)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (92 mg, 0.25 mmol) in CH2Cl2 (1 mL) and DMF (500 μL) at 0-5° C. was treated with diisopropylethylamine (87 μL, 0.50 mmol), (R)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methylbutanoic acid (64 mg, 0.28 mmol), followed by HATU (105 mg, 0.28). The reaction mixture was allowed to warm to room temperature and stir for 3 h. After this time the reaction mixture was evaporated and the residue purified by silica gel flash chromatography with 30% then 40% EtOAc/hexanes as eluant to afford the intermediate {(R)-1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carbonyl]-2-hydroxy-2-methyl-propyl}-carbamic acid tert-butyl ester as an oil (100 mg, 69%). LC/MS (Method B) 4.36 min, [M+1]+ 582.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[C:6]1(=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1>O.C(O)C>[C:6]1(=[N:2][OH:3])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: NO
Reactant: O=C1CCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=C1CCc2ccccc21
Temperature: 25 °C

Procedure:
In a 12 l four-necked flask fitted with a mechanical stirrer, a reflux condenser and a thermometer was placed 3.6 l of deionized water. Hydroxylamine hydrochloride was added. A clear, colorless solution formed (pH 2.5) to which was added 475 ml of 50% sodium hydroxide which had been diluted to 2.4 l with deionized water (pH 6.2). 1-Indanone was dissolved in 2.4 l of 3A anhydrous ethanol and added to the flask. The slightly turbid solution was heated at reflux for 15 minutes. A white solid started to precipitate at 39° C. The mixture was cooled to room temperature and then in an ice-water bath. The product was filtered off and washed with three 2 l portions of chilled water. The product was dried in a vacuum oven at 46° C. A white fluffy solid was obtained.
Reaction SMILES: [Br-].C([N+:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO.[BH4-].[Na+]>CC(C)=O>[O:20]1[CH2:19][CH2:18][CH:17]([CH2:16][O:15][CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)[CH2:22][CH2:21]1
Reactant: c1ccc(C[n+]2ccc(OCC3CCOCC3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: C1CC(OCC2CCOCC2)CCN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
1-Benzyl-4-(tetrahydro-2H-pyran-4-ylmethoxy)pyridinium bromide (1.9 g) was mixed with MeOH (35 ml), and NaBH4 (850 mg) was added thereto, followed by stirring at room temperature for 1 hour. Acetone (6 ml) was added to the reaction mixture, followed by stirring at room temperature for 30 minutes, and then activated carbon (1 g) was added thereto, followed by stirring at room temperature for 30 minutes and filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure. EtOAc and a saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with MeOH (35 ml), and ammonium formate (3 g) and 10% palladium carbon (400 mg) were added thereto, followed by stirring at 50° C. for 4 hours and filtering using Celite, and the filtrate was concentrated under reduced pressure. EtOAc and a saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain 4-(tetrahydro-2H-pyran-4-ylmethoxy)piperidine (1.01 g).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][OH:16])=[CH:4][CH:3]=1.[OH-].[Na+].CS(C)=O.Br[CH2:26][C:27]1[CH:41]=[CH:40][C:30]([C:31]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:32])=[CH:29][CH:28]=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][O:16][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:32])=[CH:40][CH:41]=2)=[CH:17][CH:18]=1
Reactant: Cc1nn(C)c(Oc2ccc(F)cc2)c1C=NO
Reactant: O=C(OC1CCCCC1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nn(C)c(Oc2ccc(F)cc2)c1C=NOCc1ccc(C(=O)OC2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
2.0 Grams (0.008 mole) of 5-(4-fluorophenoxy)-1,3-dimethylpyrazole-4-carbaldehyde oxime and 0.5 g (0.0125 mole) of powdery sodium hydroxide were added to 50 ml of dimethyl sulfoxide, and the resulting mixture was stirred for 30 minutes. To this solution was added 2.38 g (0.008 mole) of cyclohexyl 4-bromomethylbenzoate, and reaction was carried out at from 70° to 80° C. for 6 hours. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 3.0 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]COC)[C:3]=1[C:12](=[O:14])[CH3:13].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: COCOc1cccc(Cl)c1C(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1c(O)cccc1Cl
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2-chloro-6-(methoxymethoxy)phenyl)ethanone (38 g, 177.03 mmol, 1.00 equiv) in THF (380 mL) was added HCl (aq. 35 g, 2.00 equiv, 36%). The resulting mixture was allowed to react, with stirring, for 3 h at 65° C. The resulting mixture was extracted with ethyl acetate. The organic phase was separated, dried and concentrated under vacuum to give the crude title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: Fc1ccccc1I
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4ccccc4F)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-fluoro-2-iodobenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 470.2 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1>N1C=CC=CC=1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][C:21]([CH:18]2[CH2:20][CH2:19]2)=[O:22])[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2cnc3ccccc3n2)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A solution of (3-quinoxalin-2-ylphenyl)amine (2.21 g, 0.01 mol) in pyridine (10 mL) was cooled to 0° C. and cyclopropanecarbonyl chloride (0.91 mL, 0.01 mol) was added dropwise over 10 min. The reaction mixture was stirred overnight at room temperature, diluted with water (50 mL) and stirred for 30 min. The resulting solid was filtered, dried, and recrystallized from toluene to afford N-[3-(quinoxalin-2-yl)phenyl]cyclopropanecarboxamide (2.0 g, 69% yield). LCMS calculated for C18H15N3O (M+H): 290.34. found 290. 1H-NMR (DMSO-d6, 250 Mhz) δH: 10.45 (1H, br. s), 9.48 (1H, s), 8.52 (1H, s), 8.20-8.05 (2H, m), 8.05-7.80 (4H, m), 7.50 (1H, m), 1.90-1.75 (1H, m), 1.40-1.32 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:18]1[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]1>>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:18]4[CH2:21][CH:20]([C:22]#[N:23])[CH2:19]4)=[O:17])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: N#CC1CNC1
Product: N#CC1CN(C(=O)C2CCc3c(sc4ncnc(Cl)c34)C2)C1

Procedure:
150 mg (558 μmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using azetidine-3-carbonitrile to give after working up and purification 72 mg (39%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]=O)=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:22][OH:23].C([O-])(O)=O.[Na+]>C(O)C.O>[CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]=[N:22][OH:23])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(COc2ccc(C=O)nc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(COc2ccc(C=NO)nc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.8 %

Procedure:
To a solution of 5-(4-methanesulfonyl-benzyloxy)-pyridine-2-carbaldehyde (2.44 g, 8.4 mmol) in ethanol (1.5 mL) at 0° C. was added dropwise a solution of hydroxylamine hydrochloride (1.2 g) and NaHCO3 (1.6 g) in water (15 mL) and stirred at rt for 14 h. The reaction mixture was then filtered and the filtrate air-dried to yield 5-(4-methanesulfonyl-benzyloxy)-pyridine-2-carbaldehyde oxime (2.13 g, 83%) as a white solid.