Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].C(O)(=[O:7])C.N[C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:20][C:19]3[CH2:21][N:22]([C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:23][C:18]=3[CH2:17]2)=[N:14][CH:15]=1>S(=O)(=O)(O)O.C(O)(=O)C>[OH:7][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:20][C:19]3[CH2:21][N:22]([C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:23][C:18]=3[CH2:17]2)=[N:14][CH:15]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(O)cn1)C2
Reaction time: 1 h

Procedure:
Sodium nitrite (106.1 mg, 1.537 mmol) was dissolved at 0° C. in 1.84 ml of conc. sulfuric acid. Subsequently, [5-(5-aminopyridin-2-yl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl](2-trifluoromethylphenyl)methanone acetate (523 mg, 1.2 mmol), dissolved in 8 ml of acetic acid, was added dropwise, the cooling bath was removed and stirring was continued for 1 h. The reaction solution was added dropwise to 50 ml of boiling water and stirred under reflux for 5 h. After cooling, the mixture was admixed with ethyl acetate and filtered off from the residue, the water phase was adjusted to pH 4 with sodium hydrogencarbonate solution, and the organic phase was removed and concentrated. Yield: 181 mg (40%), M+H+: 376.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[S:20][C:19]([C:21]([O:23]C)=O)=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[NH:26]1[CH2:30][CH2:29][N:28]=[C:27]1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH:39][CH3:40])=[CH:33][CH:32]=1.C[Al](C)C>C(Cl)Cl>[NH:28]1[CH2:29][CH2:30][N:26]=[C:27]1[C:31]1[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][N:39]([CH3:40])[C:21]([C:19]2[S:20][C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:25])(=[O:12])=[O:11])[CH3:14])=[N:17][N:18]=2)=[O:23])=[CH:35][CH:36]=1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)s1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)s2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-thiadiazole-2-carboxylate (50 mg, 0.13 mmol), 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine (110 mg, 0.54 mmol) and trimethylaluminium (2 M in toluene, 0.27 mL) in DCM (10 mL). A portion of the crude product was purified using prep method A, then prep method B.
Reaction SMILES: [C:1]([C:9]1[CH:35]=[CH:34][C:12]([O:13][CH2:14][CH:15]([OH:33])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:20]([OH:32])[CH:19]=2)=[CH:11][C:10]=1[OH:36])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37](O)(=[O:41])[C:38]([CH3:40])=[CH2:39]>>[C:37]([O:33][CH:15]([CH2:14][O:13][C:12]1[CH:34]=[CH:35][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([OH:36])[CH:11]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:20]([OH:32])[CH:19]=1)(=[O:41])[C:38]([CH3:40])=[CH2:39]
Reactant: O=C(c1ccccc1)c1ccc(OCC(O)COc2ccc(C(=O)c3ccccc3)c(O)c2)cc1O
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)OC(COc1ccc(C(=O)c2ccccc2)c(O)c1)COc1ccc(C(=O)c2ccccc2)c(O)c1
Yield: 77.8 %

Procedure:
97 g (0.2 mole) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-2-propanol were esterified analogously to Example 1 with 103 g (1.2 moles) of methacrylic acid. Crystallization from ethanol gave 86 g (78 percent of theory) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-prop-2-yl methacrylate in the form of colorless crystals having a melting point of 138° to 139° C. and a purity of 99 percent (HPLC). The UV spectrum gave two absorption maxima at wave lengths of 287 nm (extinction 0.517; extinction coefficient 28,570) and 324 nm (extinction 0.333; extinction coefficient 18,400).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[C:9](O)=[O:10].B.C1COCC1.O>O1CCCC1>[S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=1[CH2:9][OH:10]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1C1SCCCS1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(C2SCCCS2)c(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled, stirred solution of the Compound 3b (5.00 g, 17.5 mmol) in tetrahydrofuran (100 mL) was added dropwise over 30 minutes 1.0M BH3.THF (20 mL). The solution was allowed to warm to room temperature and was stirred overnight. Additional 1.0M BH3.THF (5 mL) was added, and the solution was stirred another 4 hours. Water was added to hydrolyze the reaction, and the solution then was evaporated to dryness. The residue was dissolved in diethyl ether, and this solution was washed with a saturated solution of sodium carbonate, brine, and was dried over anhydrous magnesium sulfate. Evaporation of the solvent and recrystallization of the product from acetonitrile afforded the Compound 3c; m.p. 130°-131° C.; IR 3600 cm-1 (OH); 1H NMR (CDCl3 +D2O) δ1.8-2.2 (m, 2H, --CH2CH2CH2 --), 2.8-3.2 (m, 4H, --CH2CH2CH2 --), 4.61 (s, 2H, CH2O), 5.48 (s, 1H, SCHS), 7.7-8.3 (m, 3H, ArH).
Reaction SMILES: [CH:1]([O:4][CH2:5][C@@H:6]([OH:9])[CH2:7][OH:8])([CH3:3])[CH3:2].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:10]([O:8][CH2:7][C@H:6]([OH:9])[CH2:5][O:4][CH:1]([CH3:3])[CH3:2])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)OC[C@@H](O)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC[C@@H](O)CO[Si](C)(C)C(C)(C)C

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 34 step iii) using (2S)-3-isopropoxypropane-1,2-diol (0.80 g) (the product from step (ii) in DCM (10 mL), tert-butyldimethylsilyl chloride (1.59 g), triethylamine (1.43 mL) and 4-(dimethylamino)pyridine (50 mg) at 0° C. to give the subtitle compound as a clear, colourless oil. Yield: 1.86 g
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[NH:33][C:34]([C:36]2[N:40]3[CH:41]=[CH:42][C:43](F)=[CH:44][C:39]3=[N:38][CH:37]=2)=[O:35])[N:26]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=2)[N:25]=1>C(O)(C)(C)C>[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[NH:33][C:34]([C:36]2[N:40]3[CH:41]=[CH:42][C:43]([O:7][CH2:8][CH2:9][N:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[CH:44][C:39]3=[N:38][CH:37]=2)=[O:35])[N:26]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([CH3:53])[N:48]=2)[N:25]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(F)ccn45)cccc32)n1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C(=O)OC(C)(C)C)CC6)ccn45)cccc32)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A flask was charged with solid potassium tert-butoxide (0.07 g, 0.64 mmol), tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (0.17 g, 0.74 mmol), and tert-butanol (0.6 mL). The mixture was heated to 60° C. for 20 minutes before adding N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (0.045 g, 0.105 mmol) in one portion. The mixture was heated in a sand bath at 80° C. with stirring overnight. The reaction mixture was quenched with water and concentrated before purifying by reverse phase chromatography on a Biotage 25+C18 column, eluting with a gradient from 0-65% acetonitrile/water over 12 column volumes, to give tert-butyl 4-(2-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yloxy)ethyl)piperazine-1-carboxylate (40 mg) as a beige solid. MS (APCI), positive scan, m/z=639.1 (M+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@@H:29]1[O:46][C@H:45]([CH2:47][O:48]C(=O)C)[C@@H:40]([O:41]C(=O)C)[C@H:35]([O:36]C(=O)C)[C@H:30]1[O:31]C(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.ClCCl>[O:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:24][CH:23]=1)[C@@H:29]1[O:46][C@H:45]([CH2:47][OH:48])[C@@H:40]([OH:41])[C@H:35]([OH:36])[C@H:30]1[OH:31]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Oc1ccccc1Cc1ccc(CCOCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(CCOCc3ccccc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.4 %

Procedure:
To a solution of 2-[4-(2-benzyloxyethyl)benzyl]phenol (3.2 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (12 g) in toluene (34 mL) and dichloromethane (17 mL) was added boron trifluoride diethyl ether complex (3.8 mL), and the mixture was stirred at room temperature for 14 hours. To the reaction mixture were added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (50 mL), and to the solution was added sodium methoxide (28% methanol solution, 0.39 mL). The resulting mixture was stirred at room temperature for 2.5 hours. The solvent of the reaction mixture was removed under reduced pressure, and to the residue was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-[4-(2-benzyloxyethyl)benzyl]phenyl β-D-glucopyranoside (3.4 g).
Reaction SMILES: N.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:16]=[C:15]4[NH:17][C:18](=[O:20])[CH2:19][C:14]4=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C(O)C.[CH3:24][C:25]([CH3:27])=O>O>[C:25](=[C:19]1[C:14]2[C:15](=[CH:16][C:10]3[NH:9][C:8]([C:5]4[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH:13]=2)[NH:17][C:18]1=[O:20])([CH3:27])[CH3:24]
Reactant: CC(C)=O
Reactant: O=C1Cc2cc3nc(-c4ccncc4)[nH]c3cc2N1
Agent: N
Solvent: O
Solvent: CCO
Product: CC(C)=C1C(=O)Nc2cc3[nH]c(-c4ccncc4)nc3cc21
Reaction time: 4 h

Procedure:
Ammonia is passed up to saturation into a suspension of 0.4 g. (1.6 mmol) 2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one in 20 ml. ethanol and 10 ml. acetone and the reaction mixture then stirred for 2 hours at 60° C. Subsequently, a further 10 ml. acetone are added thereto and stirring continued for 4 hours at 60° C., whereafter the reaction mixture is evaporated, the residue is taken up in ethanol, acidified and suction filtered from the precipitate. The residue obtained is dissolved in water and rendered neutral and the crystals obtained are filtered off with suction and recrystallised from isopropanol/ethyl acetate. Yield: 40 mg. (9% of theory); m.p. >300° C.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:12]([N+:30]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:33]([CH3:34])=[CH:32][CH:31]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].Cl[C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:43]=1[C:51]([F:54])([F:53])[F:52].C(N(C(C)C)CC)(C)C>C(#N)C>[N+:48]([C:45]1[CH:46]=[CH:47][C:42]([CH:34]=[C:33]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:30]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:31]=[CH:32]2)=[C:43]([C:51]([F:52])([F:53])[F:54])[CH:44]=1)([O-:50])=[O:49]
Reactant: CCCCCCCCCCCCCCCCCC[n+]1ccc(C)c2ccccc21
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCCCCN1C=CC(=Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)c2ccccc21

Procedure:
A mixture of 1-octadecyllepidinium p-toluenesulfonate (24.6 g.), 2-chloro-5-nitrobenzotrifluoride (10 g.) and acetonitrile (700 ml.) was treated with diisopropylethylamine (20.7 g.) and refluxed for 6 hours with stirring. After filtering and evaporating, 1,4-dihydro-4-(4-nitro-2-trifluoromethylbenzylidene)-1-octadecylquinoline was formed. This colored dye was changed to the colorless compound having the formula: ##STR5## by reacting with a molar equivalent of p-toluenesulfonic acid in methanol.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:12]=[N+:11]([O-])[CH:10]=[C:9]2[NH:14][N:15]=[CH:16][C:8]=12>O>[Br:6][C:7]1[CH:12]=[N:11][C:10]([Cl:3])=[C:9]2[NH:14][N:15]=[CH:16][C:8]=12
Reactant: [O-][n+]1cc(Br)c2cn[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Clc1ncc(Br)c2cn[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phosphorus oxychloride (2 ml) was added to 4-bromo-1H-pyrazolo[3,4-c]pyridine 6-oxide (148 mg) obtained in the 1st step, followed by stirring at room temperature for 3 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. An insoluble precipitate was removed and then the solvent was distilled away under reduced pressure. A yellow solid of 4-bromo-7-chloro-1H-pyrazolo[3,4-c]pyridine (126 mg) was thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[CH:8]([CH3:14])[CH:7](C)[CH2:6][CH2:5]2.B(Br)(Br)Br.Cl[CH2:21]Cl>>[Br:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:8]([CH3:14])([CH3:21])[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1Br)CCC(C)C2C
Reactant: ClCCl
Agent: BrB(Br)Br
Product: CC1(C)CCCc2cc(Br)c(O)cc21
Temperature: 0 °C

Procedure:
To 6-bromo-7-methoxy-1,2-dimethyl-1,2,3,4-tetrahydro-naphthalene (Compound A-1 ([U.S. Pat. No. 6,613,917, incorporated herein by reference), 6.34 g, 23.56 mmol) in dichloromethane (10 mL) at −30° C. was added a solution of boron tribromide (1.0 M in dichloromethane, 47 mL, 47 mmol). After warming to 0° C. over 1 h, the reaction mixture was quenched carefully with ice water and extracted with ether. The organic layer was washed successively with water, brine, dried over Na2SO4, and concentrated in vacuo. Purification by flash column chromatography (silica gel, 5% ethyl acetate/hexane) yielded the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([C:19]3[N:20]=[N:21][N:22]([CH3:24])[N:23]=3)=[CH:14][C:13]=2[CH3:25])[N:6]=[CH:5][N:4]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[S:28]>C(#N)C.CN(C1C=CN=CC=1)C>[O:29]([C:27]([O:1][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[C:13]([CH3:25])=[CH:14][C:15]([C:19]3[N:20]=[N:21][N:22]([CH3:24])[N:23]=3)=[CH:16][C:17]=2[CH3:18])[N:6]=[CH:5][N:4]=1)=[S:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1ncnc1CO
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1ncnc1COC(=S)Oc1ccccc1
Temperature: 20 °C
Reaction time: 7 h

Procedure:
To a mixture of 5-hydroxymethyl-1-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethyl-phenoxy]-propyl]-1,2,4-triazole (343 mg, 1 mmol) in 15 ml of acetonitrile was added DMAP (244 mg, 2 mmol) and phenyl chlorothioformate (381 mg, 2.2 mmol). The mixture was stirred at 20° C. for 7 h. An additional phenyl chlorothioformate (1 equiv) was added, and the mixture was stirred for 15 h. The solvent was removed in vacuo and 5-phenoxythiocarbonyloxymethyl-1-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole was isolated and used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([Cl:27])[CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C([O-])(O)=O.[Na+]>[Cl:27][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[C:23]([F:24])([F:25])[F:26])[O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH2:7])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71.9 %

Procedure:
Entire reaction was performed under argon atmosphere using syringe septa technique. {2-[4-(3-chloro-4-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3.703 mmol, 1 eq) was dissolved in dichloromethane (20 ml) and stirred at 0° C. for 5 min. TFA (18.517 mmol, 5 eq) was added and stirring was continued overnight. Reaction mixture was diluted with 10 ml NaHCO3 (sat.) and extraction with DCM (3×20 ml) followed. Organic layers were combined and evaporated in vacuo to give 2-[4-(3-chloro-4-trifluoromethyl-phenoxy)-phenyl]-ethylamine (2.661 mmol, yield=72%, purity=99%). [M+H]+=316.21 1H NMR (300 MHz, CDCl3) δ/ppm 2.68-2.82 (m, 2H), 2.91-3.05 (m, 2H), 6.81-6.91 (m, 1H), 6.93-7.07 (m, 4H), 7.16-7.23 (m, 1H), 7.52-7.63 (m, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([NH:26][CH:27]2[CH2:30][O:29][CH2:28]2)=[O:25])=[C:22]([F:33])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:35][OH:36].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([NH:26][CH:27]2[CH2:30][O:29][CH2:28]2)=[O:25])=[C:22]([F:33])[CH:21]=1)[CH2:9]/[C:10](=[N:35]\[OH:36])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NC3COC3)c(F)c2)c2ccccc2Cl)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NC3COC3)c(F)c2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluoro-N-(oxetan-3-yl)benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 7% of the corresponding Z isomer as a colorless foam, MS (ESI+): m/z=484.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C>[C:24]([O:23][C:21](=[O:22])[CH2:20][NH:12][C:10]1[S:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1nnc(-c2ccccc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1nnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1 g (5.6 mmol) of 5-phenyl-[1,3,4]thiadiazol-2-ylamine was dissolved in 20 ml of DMF, and 3.1 g (22.6 mmol) of potassium carbonate and 1.1 g (5.6 mmol) of tert-butyl bromoacetate were added. The reaction mixture was stirred at room temperature for 16 h. After evaporation of the solvent under reduced pressure, ethyl acetate was added to the residue. The solution was washed with water, dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography. Yield: 300 mg.
Reaction SMILES: Br[C:2]([CH3:13])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F-].[K+].[N+:16]([C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]>CN(C=O)C.O>[CH3:13][C:2]([O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCOC(=O)C(C)(Br)C(=O)OCC
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Oc1cccc([N+](=O)[O-])c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
Diethyl 2-bromo-2-methylmalonate (1.0 g, 3.95 mmole) was added to a stirred suspension of potassium fluoride (0.57 g, 9.8 mmole) in dry DMF (5 mL). After stirring for 20 min at room temperature, 3-nitrophenol (0.55 g, 3.95 mmole) was added. The resulting mixture was stirred at 60° C. for 6 h, cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (3×200 mL). The organic layer was washed with aq. 1N NaOH (2×75 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to provide diethyl 2-methyl-2-(3-nitrophenoxy)malonate (0.89 g, 80%). 1H NMR (CDCl3): δ 7.92 (dd, 1H, J=2.3 and 8.2 Hz), 7.82 (t, 1H, J=2.3 Hz), 7.41 (t, 1H, J=8.2 Hz), 7.30 (dd, 1H, J=2.3 and 8.2 Hz), 4.28 (qt, 4H, J=7.0 Hz), 1.81 (s, 3H), 1.26 (t, 6H, J=7.0 Hz).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[OH:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:19]C.B(Br)(Br)Br>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[OH:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:19]
Reactant: COc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1Br
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1Br

Procedure:
To the solution of (1R,2R)-2-(7-bromo-6-methoxybenzo[d]thiazol-2-ylamino) cyclohexanol (191 mg, 0.537 mmol, 1.0 eq) in 10 mL of DCM was added 1 M solution of boron tribromide (ca. 3.0 mL, 2.68 mmol, 5.0 eq) at room temperature. The reaction mixture was refluxed for 12 hours, thereafter the mixture was diluted with saturated sodium bicarbonate (ca. 100 mL) till PH=7 and aqueous layer extracted with ethyl acetate (ca. 150 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure to give sufficiently pure crude product which was carried to next step without further purification LC/MS (m/z) [345.0] (MH+).
Reaction SMILES: C[Si]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)(C)C.[Mg].[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]2[C:22](=[O:37])[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=3)([CH3:26])[CH2:24][O:25][C:20]=2[CH:19]=1>O1CCCC1>[OH:37][C:22]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([OH:5])[CH:7]=2)[C:21]2[CH:38]=[CH:39][C:18]([O:17][CH2:16][O:15][CH3:14])=[CH:19][C:20]=2[O:25][CH2:24][C:23]1([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=1)[CH3:26]
Reactant: C[Si](C)(C)Oc1cccc(Br)c1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2=O)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)c2cccc(O)c2)cc1
Temperature: 0 °C
Yield: 66.9 %

Procedure:
Under argon atmosphere 3-bromomagnesium phenyl trimethylsilyl ether was prepared from 3-bromophenyl trimethylsilyl ether (3 g, 12.24 mmol) and magnesium turning (300 mg, 12.34 mmol) in dry tetrahydrofuran (10 ml) and cooled to 0° C. 7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran-4-one (900 mg, 2.51 mmol) dissolved in dry tetrahydrofuran (5 ml) was slowly added dropwise thereto and then refluxed for 12 hours. The reaction mixture was cooled to room temperature, quenched with water and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=2:1) to obtain 760 mg (yield: 67%) of the title compound as a foam.