Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][N:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1[C:41](NC1C=CC(C(O)=O)=CC=1)=[O:42]>>[O:42]1[CH2:1][CH2:7][C@@H:8]([CH2:9][NH:10][C:27]([C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13]3)=[O:21])=[N:24][CH:25]=2)=[O:29])[CH2:41]1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)nc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: O=C(NC[C@@H]1CCOC1)c1ccc(NC(=O)N2Cc3ccccc3C2)nc1

Procedure:
The title compound was prepared as described in Example 1C, substituting (S)-benzyl (tetrahydrofuran-3-yl)methylcarbamate for 3-phenylpropan-1-amine and 6-(isoindoline-2-carboxamido)nicotinic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.27 (s, 1H), 8.74 (d, J=2.1 Hz, 1H), 8.60 (t, J=5.7 Hz, 1H), 8.14 (dd, J=8.8, 2.4 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.41-7.27 (m, 4H), 4.89 (m, 4H), 3.75 (m, 1H), 3.69 (m, 1H), 3.62 (m, 1H), 3.48 (dd, J=8.5, 5.3 Hz, 1H), 3.25 (m, 2H), 2.48 (m, 1H), 1.95 (m, 1H), 1.61 (m, 1H); MS (ESI(+)) m/e 367 (M+H).
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([F:14])=[CH:6][C:5]=1[CH2:15]Br.[CH2:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1)[CH3:19].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:14][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([C:10]([F:11])([F:12])[F:13])[CH:8]=1)[C:3](=[O:17])[N:25]([CH2:24][C:23]1[CH:26]=[CH:27][C:20]([CH2:18][CH3:19])=[CH:21][CH:22]=1)[CH2:15]2
Reactant: CCc1ccc(CN)cc1
Reactant: COC(=O)c1c(CBr)cc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1ccc(CN2Cc3cc(F)cc(C(F)(F)F)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 333.5 %

Procedure:
A mixture of 4-fluoro-2-bromomethyl-6-trifluoromethyl-benzoic acid methyl ester (0.100 g, 0.32 mmol), 4-ethyl-benzylamine (0.06 mL, 0.42 mmol), and K2CO3 (0.088 g, 0.64 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-2-(4-ethyl-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.36 g, 33%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.22 (t, 3H), 2.65 (q, 2H), 4.27 (s, 2H), 4.78 (s, 2H) 7.20-7.56 (m, 6H). GC-MS: m/z 337 (M)+, 318 (M−19)+.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[F:15][C:16]([F:50])([F:49])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[CH:34]=[C:35]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[CH:40]=3)[CH:36]=[CH:37][CH:38]=2)[N:18]=1>C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:45]([C:41]1[CH:40]=[C:39]([C:35]2[CH:36]=[CH:37][CH:38]=[C:33]([C:19]3[N:18]=[C:17]([C:16]([F:15])([F:49])[F:50])[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:25][CH:24]=4)[N:20]=3)[CH:34]=2)[CH:44]=[CH:43][CH:42]=1)(=[O:46])=[O:47]
Reactant: OCCNCCO
Reactant: O=S(=O)(Cl)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1)N(CCO)CCO
Temperature: 0 °C
Yield: 52.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of diethanolamine (0.12 g, 1.14 mmol), triethylamine (0.06 ml, 0.42 mmol) and THF (2 ml) was added drop wise a solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonyl chloride (example I.3) (0.21 g, 0.39 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (diethyl ether/hexane) yielded the title compound as a white solid (0.125 g, 53%). MS (ISP) 611.6 [(M+H)+]; mp 111.5° C.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br.Br[CH2:45][C:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1)=[O:47]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:45][C:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)=[O:47])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3ccccn3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(pyridin-2-yl)ethanone hydrobromide and isolated as dark-brown solid. MS(m/e): 402.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]2[N:6]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]([N:21]([CH3:33])[CH2:22][CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[O:20])[N:11]=3)[N:7]=[N:8][C:4]=2[C:3]=1[O:36][C:37]1[CH:42]=[C:41]([C:43]#[N:44])[CH:40]=[C:39]([Cl:45])[CH:38]=1>C(O)(C(F)(F)F)=O>[Cl-:1].[Cl:1][C:2]1[CH:35]=[CH:34][C:5]2[N:6]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[N:12]([C:19]([N:21]([CH3:33])[CH2:22][CH2:23][NH2+:24][CH3:25])=[O:20])[N:11]=3)[N:7]=[N:8][C:4]=2[C:3]=1[O:36][C:37]1[CH:42]=[C:41]([C:43]#[N:44])[CH:40]=[C:39]([Cl:45])[CH:38]=1
Reactant: CN(CCN(C)C(=O)n1nc(Cn2nnc3c(Oc4cc(Cl)cc(C#N)c4)c(Cl)ccc32)c2cccnc21)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: C[NH2+]CCN(C)C(=O)n1nc(Cn2nnc3c(Oc4cc(Cl)cc(C#N)c4)c(Cl)ccc32)c2cccnc21
Product: [Cl-]
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
tert-butyl {2-[[(3-{[5-chloro-4-(3-chloro-5-cyanophenoxy)-1H-1,2,3-benzotriazol-1-yl]methyl}-1H-pyrazolo[3,4-b]pyridin-1-yl)carbonyl](methyl)amino]ethyl}methylcarbamate (125 mg, 0.192 mmol) was dissolved in TFA (5 mL). After 20 minutes, the reaction was concentrated and the resulting residue was purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. Product fractions were concentrated under reduced pressure and the resulting solid was dissolved in MeCN (3 mL), cooled to −78° C. and 1N HCl (5 mL) added. This froze and was lyophilized to yield the title compound. 1H NMR (DMSO-d6) δ 8.68 (dd, J=4.5 Hz, J=1.5 Hz, 1H), 8.57 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.11 (s, 1H), 7.96 (m, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.72 (m, 1H), 7.58 (m, 1H), 7.44 (dd, J=4.6 Hz, J=8.0 Hz, 1H), 7.35 (m, 1H), 7.28 (m, 1H), 6.50 (s, 2H), 3.70 (s, 3H), 3.20 (s, 2H), 3.00 (s, 2H), 2.20 (m, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:11]1[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][CH:16]=1.[CH2:33]([Mg]Cl)[CH2:34][CH2:35][CH3:36]>O1CCCC1.CN1CCCC1=O.C(OCC)C>[CH2:33]([C:13]1[CH:12]=[C:11]([CH:10]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCC[Mg]Cl
Reactant: CN1CCC(OC(c2cccc(OS(=O)(=O)C(F)(F)F)c2)c2nc3ccccc3s2)CC1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCCCc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3s2)c1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a mixture of trifluoromethanesulfonic acid 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester (110 mg) and ferric acetylacetonate (4 mg) in a mixture of tetrahydrofurane (4.5 mL) and N-methylpyrrolidone (0.25 mL) cooled at 0° C. is added a 2M solution of butylmagnesium chloride in tetrahydrofurane (150 μL). The mixture is stirred at room temperature for 25 min, then warmed at 30° C. for 15 min. A second addition of butylmagnesium chloride in tetrahydrofurane (150 μL) is performed. The mixture is then diluted with diethyl ether and quenched with 0.5N hydrochloric solution. The aqueous phase is extracted with diethyl ether, then ethyl acetate. Organic phases are pooled, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient heptane/ethyl acetate from 99/1 to 90/10). The product is then refluxed in methanol and concentrated to give 2-[(3-butylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]3[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:12]3[N:11]=2)=[CH:6][CH:5]=1.[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[OH:41][CH2:40][C:39]([NH:38][S:35]([C:31]1[CH:30]=[C:29]([NH:28][C:23]([C:22]2[CH:21]=[N:20][N:13]3[C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:27])([F:1])[F:26])=[CH:9][CH:8]=4)=[N:11][C:12]=23)=[O:24])[CH:34]=[CH:33][CH:32]=1)(=[O:37])=[O:36])([CH3:43])[CH3:42]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-trifluoromethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.19) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Yellow solid. MS (ISP) 618.3 [(M+H+]; mp 212° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:21]=[C:15]3[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][N:14]3[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[BrH:22].CC(O)=O>>[Br:22][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:21]=[C:15]3[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][N:14]3[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: Br
Reactant: CN1CCn2nc(Nc3cc(Cl)nn4ccnc34)cc2C1
Solvent: CC(=O)O
Product: CN1CCn2nc(Nc3cc(Br)nn4ccnc34)cc2C1
Temperature: 150 °C

Procedure:
To an autoclave was charged 124f (800 mg, 2.6 mmol)) and HBr/AcOH (60 mL). It was heated at 150° C. for 18 h. The reaction mixture was concentrated under reduced pressure to give black oil. The oil was recrystallized from methanol (30 mL)/dichloromethane (30 mL)/petroleum ether (90 mL) to 124g as a yellow solid (600 mg, 66%). MS-ESI: [M+H]+ 348.1
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]4[NH:39][C:38](=[O:40])[O:37][N:36]=4)=[CH:25][CH:24]=3)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=[C:16]2[CH3:44])=[CH:11][CH:10]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:44][C:16]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C:2]3=[O:1])=[CH:14][CH:13]=2)[C:20](=[O:21])[C:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][C:38](=[O:40])[O:37][N:36]=3)=[CH:25][CH:24]=2)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=1
Reactant: CCCc1nc(C)n(-c2ccc(O[C@H]3CCCC[C@@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(OC3CCCCC3=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 15 h
Yield: 90.3 %

Procedure:
To a solution of 3-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.30 g) in methylene chloride (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.32 g), and the mixture was stirred for 15 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.27 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][CH2:25][O:26][CH3:27])[N:14]([CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][C:19]3=[O:23])[C:10]=2[C:9]2[CH:8]=[C:7]([CH2:28][CH2:29][N:30]3C(=O)C4C(=CC=CC=4)C3=O)[CH:6]=[CH:5][C:4]=2[N:3]=1.O1CCCC1.O.NN>C(O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][CH2:25][O:26][CH3:27])[N:14]([CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][C:19]3=[O:23])[C:10]=2[C:9]2[CH:8]=[C:7]([CH2:28][CH2:29][NH2:30])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COCCc1nc2c(N)nc3ccc(CCN4C(=O)c5ccccc5C4=O)cc3c2n1CCCN1CCCC1=O
Agent: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COCCc1nc2c(N)nc3ccc(CCN)cc3c2n1CCCN1CCCC1=O
Temperature: 25 °C
Yield: 38.6 %

Procedure:
2-(2-{4-Amino-2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}ethyl)-1H-isoindole-1,3(2H)dione (2.2 g, 4.1 mmol) was dissolved in 2:1 ethanol:tetrahydrofuran (40 mL), combined with hydrazine hydrate (410 mg, 8.2 mmol) and heated at reflux temperature for three hours. Additional hydrazine hydrate (0.25 mL) was added and the solution was refluxed for an additional 1.5 hours. The reaction was cooled to ambient temperature, filtered and the filtrate concentrated under reduce pressure. Purification by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-40% CMA:chloroform gradient over 3.8 L) provided 650 mg of 1-{3-[4-amino-8-(2-aminoethyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as an off-white solid. MS (ESI) m/z 411 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1)=[N:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)C.CN1C=CN=C1.[OH-].[Na+].CO>O1CCCC1>[NH2:21][C:18]1[S:19][CH:20]=[C:16]([C:5](=[N:6][O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4]([OH:22])=[O:3])[N:17]=1
Reactant: CCOC(=O)C(=NOCc1ccc(F)cc1)c1csc(N)n1
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCc2ccc(F)cc2)C(=O)O)cs1
Yield: 94.9 %

Procedure:
Ethyl-2-(2-aminothiazol-4-yl)-2-(4-fluorobenzyloxyimino)-acetate (syn isomer, 25.5 g.), 1-methylimidazole (1.3 g.), 1 N sodium hydroxide solution (118.3 ml.), methanol (250 ml.) and tetrahydrofuran (200 ml.) were treated in similar manner to that of Example p-(4) to give 2-(2-aminothiazol-4-yl)-2-(4-fluorobenzyloxyimino)acetic acid (syn isomer, 22.11 g.).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH3:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][SH:50]>>[CH2:49]([S:50][C:18](=[O:19])[CH2:17][S:14](=[O:16])(=[O:15])[NH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:11])[CH3:12])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH3:38]
Reactant: CCCCCCCCCCCCS
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CCCCCCCCCCCCSC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with dodecylthiol, mp 58°-60° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[Si:18]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
20.0 g (115 mmol) of tert-butyl 3-hydroxyazetidine-1-carboxylate and 9.43 g (139 mmol) of imidazole were initially charged in 200 ml of anhydrous DMF, and 34.91 g (127 mmol) of tert-butyl(diphenyl)silyl chloride were added at RT. After the reaction mixture had been stirred at RT for 18 h, it was poured into 3.2 liters of water and then extracted three times with approx. 1 liter each time of diethyl ether. The combined organic extracts were washed successively with saturated sodium hydrogencarbonate solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the solvent was removed on a rotary evaporator. The remaining residue was stirred with 100 ml of pentane for a few minutes. Subsequently, the solid was filtered off with suction and dried under high vacuum. 29.18 g (61% of theory) of the title compound were obtained.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)[OH:16].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:30]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[CH:35][C:31]=2[C:32](O)=O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>O>[CH3:29][O:28][C:27]1[C:26](=[O:16])[C:25]2[C:24](=[CH:23][C:22]=1[O:21][CH3:20])[C:30]1[C:31](=[CH:35][C:36]([O:41][CH3:42])=[C:37]([O:39][CH3:40])[CH:38]=1)[CH:32]=2
Reactant: O=P(O)(O)O
Reactant: COc1ccc(-c2cc(OC)c(OC)cc2C(=O)O)cc1OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: COC1=C(OC)C(=O)C2=Cc3cc(OC)c(OC)cc3C2=C1
Temperature: 100 °C

Procedure:
Polyphosphoric acid which had been newly prepared from diphosphorus pentaoxide (50 g) and phosphoric acid (50 ml) was heated at 100° C. With stirring, 2-(3,4-dimethoxyphenyl)-4,5-dimethoxybenzoic acid (7.5 g) was added thereto as it is (in the crystal form) in several portions. After stirring at 100 to 120° C. for 2 hours, the reaction solution was poured into water (1.5 liter) and extracted with chloroform. The extract was washed with 2% aqueous sodium hydroxide solution, water and a saturated saline solution, then dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform) and recrystallized from ethyl acetate-n-hexane to give 5.0 g of 2,3,6,7-tetramethoxyfluorenone as an orange needle-like crystal.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([N:19]([CH3:21])[CH3:20])([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[OH:27][CH2:26][CH2:25][CH2:24][NH:23][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([N:19]([CH3:21])[CH3:20])([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(F)cc1)N(C)C
Reactant: NCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(NCCCO)cc1)N(C)C
Reaction time: 12 h

Procedure:
15.0 g (0.050 mol) of 1-(4-fluorophenyl)-2-dimethylamino-2-benzyl-butan-1-one and 26.3 g (0.35 mol) of 3-amino-1-propanol are dissolved in 30 ml of dry dimethylacetamide, and the solution is heated up to 150° C. together with 13.8 g (0.1 mol) of potassium carbonate, and stirred overnight (about 12 h). After the solution is cooled down, it is poured into 300 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the ethyl acetate, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:1) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 0.68 (t, 3H), 1.52 (br, 1H), 1.82-1.94 (m, 3H), 2.00-2.07 (m, 1H), 2.35 (s, 6H), 3.17 (d, 1H), 3.20 (d, 1H), 3.32-3.37 (m, 2H), 3.81-3.85 (m, 2H), 4.42 (br, 1H), 6.52 (d, 2H), 7.14-7.28 (m, 5H), 8.32 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:14][CH3:15].Br[CH2:17][CH2:18][CH:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.[I-].[K+]>CC(=O)CC>[O:22]1[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:19]([CH2:18][CH2:17][N:11]2[CH2:10][CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:14][CH3:15])[CH:4]=3)[CH2:13][CH2:12]2)[CH2:20][CH2:21]1
Reactant: COc1cc(C2CCNCC2)ccc1O
Reactant: BrCCC1CCOc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cc(C2CCN(CCC3CCOc4ccccc43)CC2)ccc1O

Procedure:
1-[2-(3,4-Dihydro-1(2H)-benzopyran-4-yl)ethyl]-4-(4-hydroxy-3-methoxyphenyl)piperidine is prepared by proceeding as in Example 48 but starting with 4-(4-hydroxy-3-methoxyphenyl)piperidine, 4-(2-bromoethyl)-3,4-dihydro-2H-benzopyran (0.49 g) and potassium iodide (0.5 g) in 2-butanone (35 cc).
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:12][CH2:13][NH:14][C:15](=O)[CH3:16])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>O.C(O)C>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH3:16][C:15]1[C:9]2[N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:10]=2)[CH2:12][CH2:13][N:14]=1
Reactant: CC(=O)NCCn1cccc1-c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: CC1=NCCn2c1ccc2-c1ccccc1
Yield: 57 %

Procedure:
N-[2-(2-Phenylpyrrol-1-yl]-ethyl]acetamide (5.0 g) was added to 30 ml of phosphorus oxychloride under argon and the mixture was boiled under reflux for 1 hour. The cooled mixture was hydrolyzed with 100 ml of 2N sodium hydroxide solution and 230 ml of 28% sodium hydroxide solution (cooling with ice), diluted with 2000 ml of water and extracted with methylene chloride (1×350 ml, 3×200 ml). The organic phases were combined, dried with MgSO4 and freed from solvent. 1.0 g of a total of 4.5 g of crude product was dissolved in a 30-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There was obtained 0.9 g (57%) of 3,4-dihydro-1-methyl-6-phenylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 175° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20].O>CN1CCCC1=O>[F:11][C:8]1[CH:9]=[CH:10][C:3]2[C:2]([NH:1][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[CH:6][S:5][C:4]=2[CH:7]=1
Reactant: Nc1csc2cc(F)ccc12
Reactant: Fc1cnccc1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc2c(Nc3ccncc3F)csc2c1
Yield: 82.6 %

Procedure:
A solution of 3-amino-6-fluorobenzo[b]thiophene (10 g, 60 mmol) and 4-chloro-3-fluoropyridine hydrochloride (12 g, 71 mmol) in 150 mL of 1-methyl-2-pyrrolidinone was stirred at 90°-95° for 2.5 h, and thereafter cooled, stirred with water and extracted with ether. The aqueous layer was basified with 30% aqueous ammonium hydroxide and extracted with ether. The organic extract was washed with water and saturated sodium chloride solution, and dried (anhydrous magnesium sulfate), filtered and concentrated to give 13 g of a solid. Elution through silica with 10% ethyl acetate in dichloromethane via flash column chromatography yielded 7 g (44.6%) of a white solid, mp 155°-157° C. Recrystallization of 2 g from acetonitrile afforded 1.3 g (29%) of white needles, mp 158°-159° C.