Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([CH:20]=O)=[CH:17][CH:18]=2)[CH:13]=[N:12]1.N1CCCCC1>CCO>[NH:11]1[C:19]2[C:14](=[CH:15][C:16](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2[nH]ncc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]ncc2c1
Temperature: 90 °C
Yield: 7.7 %

Procedure:
A scintillation vial was charged with indolin-2-one (67 mg, 0.500 mmol), 1H-indazole-5-carbaldehyde (73 mg, 0.550 mmol), piperidine (5.0 uL, 0.076 mmol) and EtOH (2 mL). The reaction was then heated to 90° C. for 2 hrs. The EtOH was removed and the product purified by preparatory reverse-phase HPLC to give 10 mg, 7.6% of the title compound. 1H NMR (400 MHz, CD3OD) δ 8.20-8.18 (m, 2H), 7.89 (s, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.71-7.67 (m, 2H), 7.24 (t, J=7.4 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 6.90 (t, J=7.5 Hz, 1H); MS ESI 262.0 [M+H]+, calcd for [C16H11N3O+H]+ 262.10.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)=[CH:7][CH:6]=1.Cl[CH2:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C)C=O>[O:21]=[C:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:22])[F:23])=[CH:10][CH:9]=3)[CH:12]=2)[N:17]1[CH2:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Reactant: CCOC(=O)c1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(CN2C(=O)CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)c1
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a mixture of 95% dry sodium hydride (18 mg, 0.75 mmol) in anhydrous N,N-dimethylfounamide (4 mL) at room temperature was added a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (90 mg, 0.31 mmol) (PT-010 made as in Example 1B, above) in anhydrous N,N-dimethylformamide (1 mL). The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of ethyl 3-(chloromethyl)benzoate (100 mg, 1.00 mmol) in N,N-dimethylformamide (1.0 mL). The reaction mixture was stirred at room temperature until most of the starting material was converted (checked by LCMS), then it was quenched by addition of methanol (5 mL) The reaction mixture was concentrated under a reduced pressure, diluted with ethyl acetate (50 mL), and the organic phase washed with 2N sodium carbonate (20 mL), 30% ammonium chloride (20 mL), brine (20 mL), dried over magnesium sulfate, and the solvent removed under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL) and subjected to reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford ethyl 3-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoate (compound no. 91) (108 mg, 0.24 mmol, 77%) (PT-094). LCMS mz 455.0 (M+H), 476.0 (M+Na), anal HPLC>95% in purity. 1H NMR (400 MHz; CDCl3) δ 7.94 (m, 2H); 7.64 (m, 4H); 7.41 (m, 3H); 7.30-7.37 (m, 1H); 6.92 (d, J=8.6 Hz, 1H); 5.27 (s, 2H); 4.37 (q, J=7.0 Hz, 2H); 3.08 (m, 2H), 2.86 (m, 2H); 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCCCC>[CH:1]([C@H:14]1[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][CH2:20]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCC
Product: O[C@@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(1S,4S,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (0.3 g, 1.13 mmol) in dry pentane (10 ml) was added to a suspension of LiAlH4 (0.21 g, 5.64 mmol) in dry pentane (20 ml). The resulting reaction mixture was stirred under N2 for 20 hr at room temperature, and then quenched with 10% NaOH, diluted with ethyl acetate (30 ml), and the precipitate removed by filtration. The organic phase was washed with brine and dried over anhydrous Na2SO4. Removal of solvent followed by flash chromatography of the crude product produced pure (3R,6S)-6-benzhydryl-tetrahydro-pyran-3-ol, 33a, 0.23 g (75%, [α]D=(−)−61.6, c=1, MeOH).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[C:16]1([C:36]3[C:27](=[CH:28][C:29]4[O:34][CH2:33][CH2:32][O:31][C:30]=4[CH:35]=3)[O:26][CH2:25]1)[C:17](=[O:24])[N:18]2[CH3:23])(=[O:13])[CH3:12].O>O1CCCC1>[CH3:23][N:18]1[C:19]2[C:15](=[C:14]([C:11](=[O:13])[CH2:12][C:3]([O:7][CH2:8][CH3:9])=[O:10])[CH:22]=[CH:21][CH:20]=2)[C:16]2([C:36]3[C:27](=[CH:28][C:29]4[O:34][CH2:33][CH2:32][O:31][C:30]=4[CH:35]=3)[O:26][CH2:25]2)[C:17]1=[O:24]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccc2c1C1(COc3cc4c(cc31)OCCO4)C(=O)N2C
Temperature: 25 °C
Yield: 39.6 %

Procedure:
To a suspension of sodium hydride (60% w/w dispersion in mineral oil, 0.11 g, 2.8 mmol) in anhydrous tetrahydrofuran (10 mL) at ambient temperature was added diethyl carbonate (0.26 mL, 2.1 mmol) and the mixture was heated at reflux for 5 min. 4′-Acetyl-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.50 g, 1.4 mmol) was added in one portion and the reaction mixture was heated at reflux for 16 h, allowed to cool to ambient temperature and poured into water (75 mL). The mixture was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography and eluted with a 0% to 10% gradient of ethyl acetate in dichloromethane, followed by recrystallization from dichloromethane/diethyl ether to afford ethyl 3-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)-3-oxopropanoate (0.235 g, 39%) as a pale yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.50-7.43 (m, 2H), 7.14-7.09 (m, 1H), 6.51 (s, 1H), 6.02 (s, 1H), 4.97-4.78 (m, 2H), 4.20-4.03 (m, 6H), 3.89 (d, J=15.6 Hz, 1H), 3.65 (d, J=15.6 Hz, 1H), 3.29 (s, 3H), 1.16 (t, J=7.1 Hz, 3H); MS (ES+) m/z 445.8 (M+23).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]3[CH:32]=[CH:31][C:20]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[CH:19][CH:18]=3)=[C:11]([N+:33]([O-])=O)[CH:10]=2)=[O:8])=[CH:4][C:3]=1[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:33][C:11]1[CH:10]=[C:9]([C:7]([C:5]2[S:6][C:2]([Br:1])=[C:3]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:4]=2)=[O:8])[CH:14]=[CH:13][C:12]=1[C:15]#[C:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccc(C(=O)OCc4ccccc4)cc3)c([N+](=O)[O-])c2)sc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccc(C(=O)OCc4ccccc4)cc3)c(N)c2)sc1Br
Yield: 105.2 %

Procedure:
To a solution of 3 (450 mg, 0.71 mmol) in EtOAc (10 mL) was added stannous chloride dihydrate (642 mg, 2.84 mmol). The resulting mixture was refluxed for one hour under N2. The reaction mixture was then poured onto ice (5 g), and basified with a saturated NaHCO3 solution to pH 8. The white milky mixture was filtered through a Celite pad to remove tin oxides. The organic layer from the filtrate was dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the crude product gave the desired intermediate benzyl 4-((2-amino-4-(5-bromo-4-(2-ethoxy-2-oxoethyl)thiophene-2-carbonyl)phenyl)ethynyl)benzoate as a yellow foam (450 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 7.51-7.36 (m, 7H), 7.22-7.18 (m, 2H), 5.38 (s, 2H), 4.18 (q, J=7.2 Hz, 2H), 3.64 (s, 2H), and 1.27 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 186.72, 169.84, 166.01, 148.31, 143.21, 138.58, 136.12, 136.05, 135.39, 132.55, 131.71, 130.02, 129.98, 128.90, 128.62, 128.51, 127.71, 122.93, 118.70, 114.66, 111.47, 96.66, 88.41, 67.21, 61.63, 53.75, 35.32, and 14.44.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]1=[O:26].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](Cl)=[O:38]>O1CCOCC1>[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37]([NH:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]1=[O:26])=[O:38]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc3c(c2N)NC(=O)CO3)c1=O
Solvent: C1COCCO1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc3c(c2NC(=O)c2ccc4ccccc4c2)NC(=O)CO3)c1=O

Procedure:
3-[5-Amino-7-fluoro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-1-methyl-6-trifluoromethyl-2,4-(1H, 3H)-pyrimidinedione (0.37 g) and 2-naphthoyl chloride (0.21 g) were mixed in dioxane (15 ml) and the mixture was refluxed for 6 hr. After evaporation of solvent, the residue was recrystallized from toluene (0.20 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.O>C1COCC1>[C:3]1([CH2:2][CH2:2][C:3]2[C:15]3[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]=3[CH:6]=[CH:5][CH:4]=2)[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1cccc2c1Cc1ccccc1-2
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cc1c(CCc3cccc4c3Cc3ccccc3-4)cccc1-2

Procedure:
5.1 g, 19.6 mmol 1-bromomethylfluorene dissolved in 50 ml THF was added dropwise to 0.24 g, 9.9 mmol Mg in 10 ml THF. After addition the Grignard was refluxed for 2 hrs, cooled and water/aqueaous HCl added. After work-up this afforded 1.5 g of CH2CH2(1-fluorenyl)2 as a beige powder. 1H NMR (CDCl3): δ 3.81 ppm (CH2), 3.14 ppm (CH2).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](OCC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:24][NH2:25])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)NN)ncn2-c2cccc(Cl)c2C1=O
Yield: 108.5 %

Procedure:
50 g (156.4 mmol) of ethyl 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate were stirred at boiling temperature for 6 hours with 90 ml (1.85 mol) of hydrazine hydrate in 500 ml of ethanol. By cooling to -10°, filtering the suspension under suction and drying the crystallizate there were obtained 51.9 g (100%) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide of m.p. 287°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.CN(C)C=O>O>[O:1]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: OCc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1.24 g (0.01 mole) of 4-hydroxymethylphenol, 1.8 g (0.012 mole) of tert-butyldimethylsilyl chloride, 1.7 g (0.025 mole) of imidazole and 3 ml of dimethylformamide was stirred under nitrogen at room temperature for 12 h. The reaction mixture was poured into water and extracted with three portions of ether. Ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (Na2SO4). The ether solution was concentrated in-vacuo and the resultant crude product was purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:16])[CH:11]3[CH2:14][CH3:15])[C:8]=2[C:17]([O:19]CC2C=CC([N+]([O-])=O)=CC=2)=[O:18])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+:36]>O1CCOCC1.O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:16])[CH:11]3[CH2:14][CH3:15])[C:8]=2[C:17]([O-:19])=[O:18])=[CH:30][CH:31]=1.[Na+:36]
Reactant: CCC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Oc3ccc(Cl)cc3)SC12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC1C(=O)N2C(C(=O)[O-])=C(Oc3ccc(Cl)cc3)SC12

Procedure:
A mixture of a solution of 205 mg of 4-nitrobenzyl 3-(4-chlorophenoxy)-6-ethyl-7-oxo-4-thia-1-azabicyclo-[3,2,0]hept-2-ene-2-carboxylate in dioxan and 37.5 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:13](=[O:33])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[CH3:12])C1C=CC=CC=1.C1(C)C=CC=CC=1>C(O)(=O)C>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]1[C:16]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:33])[CH:11]([CH3:12])[N:10]=1
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
35 g of the foregoing propionoanilide are heated to reflux in 40 ml of glacial acetic acid and 200 ml of absolute toluene for 15 minutes. The residue obtained after distillation of the solvent is treated with methylene chloride and 10% sodium bicarbonate solution. The methylene chloride solution is washed twice with 10% sodium bicarbonate solution and once with water, dried over sodium sulfate, filtered and concentrated. The residue is taken up in benzene, some racemate formed crystallising out and being filtered off. The benzene solution is evaporated and the residue crystallised from ether to give (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one which melts at 198°-200° C and exhibits a rotation of [α]25D =+252.1° (in methylene chloride, 1%).
Reaction SMILES: ClC1C=CC=C[C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9]1.C(O)(=O)C.[CH2:23]([C:27](OCC)(OCC)[O:28][CH2:29][CH3:30])[CH2:24][CH2:25][CH3:26]>C(#N)C>[CH2:29]([O:28]/[C:27](=[C:11]1/[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9][N:8]([CH3:3])[C:12]/1=[O:13])/[CH2:23][CH2:24][CH2:25][CH3:26])[CH3:30]
Reactant: COC(=O)Cc1cc(O)n(-c2ccccc2Cl)n1
Reactant: CCCCC(OCC)(OCC)OCC
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCC/C(OCC)=C1/C(=O)N(C)N=C1CC(=O)OC
Temperature: 70 °C

Procedure:
The mixture of the above obtained methyl (5-hydroxy-1-methyl-1H-pyrazol-3-yl)acetate (Compound of Formula (IV), 0.80 g) in acetonitrile (5 mL), glacial acetic acid (21 μl, 0.1 equiv.) and BuC(OEt)3 (3 eq.) was heated at 70° C. for 1 h 15. The resulting red solution was concentrated in vacuo to afford a red syrup that was washed with cyclohexane and then dried in vacuo. Due to its relative instability, no further purification of methyl [(4Z)-4-(1-ethoxypentylidene)-1-methyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate was conducted (1.0 g, quantitative yield). MS (ESI+): 283.4; MS (ESI−): 281.3.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)[C:6]([O:15][CH3:16])=[CH:5][C:3]=1[NH2:4].[C:17](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:18]>ClCCl>[F:1][C:2]1[C:3]([N:4]=[C:17]=[S:18])=[CH:5][C:6]([O:15][CH3:16])=[C:7]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)[CH:8]=1
Reactant: COc1cc(N)c(F)cc1-n1cnc(C)n1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cc(N=C=S)c(F)cc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.6 %

Procedure:
Step B (3): Dichloromethane (125 mL) was added to a flask charged with 2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (1.07 g, 4.82 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (1.12 g, 4.82 mmol). The resulting mixture was stirred for 24 h at rt and concentrated in vacuo. The crude residue was purified using silica gel chromatography (0-5% EtOAc/chloroform, linear gradient over 36 min, flow 25 mL/min) to afford 1-(5-fluoro-4-isothiocyanato-2-methoxyphenyl)-3-methyl-1H-1,2,4-triazole (950 mg, 75% yield) as a yellow solid. LC-MS (M+H)+ 265.1. 1H NMR (500 MHz, chloroform-d) δ ppm 8.74 (s, 1 H) 7.75 (d, J=10.07 Hz, 1 H) 6.84 (d, J=6.41 Hz, 1 H) 3.94 (s, 3 H) 2.48 (s, 3 H).
Reaction SMILES: C([N:5]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)CCC.[C:31]1(N)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN1CCCC1=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:16]2[C:15]([NH:5][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[N:17]2)=[CH:25][CH:26]=1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2nc3ccccc3c2Nc2ccccc2)cc1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with phenylamine ([62-53-3]) in N-methyl 2-pyrrolidone for 48 h at 175° C. in a sealed tube to give the title compound as brown solid. MS: m/e=320.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:19]=[CH:18][CH:17]=[C:16](F)[C:13]=2[C:14]#[N:15])(=[O:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH3:21].CCOC(C)=O>CO>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]([S:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=2)(=[O:11])=[O:10])[C:13]=1[C:14]#[N:15]
Reactant: N
Reactant: Cc1cc(C)cc(S(=O)(=O)c2cccc(F)c2C#N)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C)cc(S(=O)(=O)c2cccc(N)c2C#N)c1
Temperature: -78 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
2-[(3,5-Dimethylphenyl)sulfonyl]-6-fluorobenzonitrile (Example 20) (0.5 g 1.7 mmol) was dissolved in 80 ml of methanol and chilled to -78° C. Condensed ammonia (20 ml, 15.4 g, 905 mmol) was added and the mixture was heated to150° C. in a sealed Parr bomb for 24 h. Chromatography on silica gel (flash; Hex/EtOAc 1:1) provided 0.28 g (56%) of 2-amino-6-[(3,5-dimethylphenyl)sulfonyl]benzonitrile: mp 208°-209° C.;; NMR (Me2SO-d6, 200 MHz) δ 2.36 (s, 6H), 6.59 (br s, 2H), 7.10 (apparent d, 1H), 7.3-7.4 (m, 2H) 7.54 (apparent d, 1H), 7.58 (m, 2H); mass spec (CI) M+ +1=287. Anal. Calc. for C15H14N2O2S: C, 62.92; H, 4.93; N: 9.78; S, 11.20. Found: C, 63.02; H, 4.98; N, 9.72; S, 11.12.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].[C:18]([C:21]1[O:25][C:24]2[C:26]([C:30]3[CH:35]=[C:34]([CH2:36][CH3:37])[CH:33]=[C:32]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:31]=3[O:42][CH2:43][CH2:44][CH3:45])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)(=O)[CH3:19].O>CN(C=O)C>[CH2:4]([O:5][C:6](=[O:7])[C:8]([F:9])=[C:18]([C:21]1[O:25][C:24]2[C:26]([C:30]3[CH:35]=[C:34]([CH2:36][CH3:37])[CH:33]=[C:32]([C:38]([CH3:41])([CH3:40])[CH3:39])[C:31]=3[O:42][CH2:43][CH2:44][CH3:45])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)[CH3:19])[CH3:3]
Reactant: CCCOc1c(-c2cccc3cc(C(C)=O)oc23)cc(CC)cc1C(C)(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(-c2cccc3cc(C(C)=C(F)C(=O)OCC)oc23)cc(CC)cc1C(C)(C)C
Reaction time: 0.25 h

Procedure:
To a mixture of 43 mg (0.89 mmol) of NaH in 1 mL of dry DMF was added 216 mg (0.89 mmol, 0.15 mL) of triethyl 2-fluoro-2-phosphonoacetate diluted in 1 mL of dry DMP at 0° C. After the gas evolution ceased, the solution was stirred at this temperature for 15 minutes and 0.296 mmol of 2-acetyl-7-(2-propoxy-3-tert-butyl-5-ethylphenyl) benzo[b]furan diluted in 1 mL of dry DMF was added dropwise. The reddish solution was stirred to 0° C. until completion (TLC monitoring). After cooling, water was added and the mixture as extracted with ethyl acetate. The organic layer was washed with water and brine and dried over MgSO4. The solvents were evaporated under reduced pressure, and the residual oil was purified over silica gel (eluent: ethyl acetate/hexane: 5/95) to afford 2-fluoro-3-[7-(2-propoxy-3-tert-butyl-5-ethylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid ethyl ester as a clear yellow oil. 1H NMR (CDCl3), δ: 7.52 (d, J=7.8 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.39 (d, J=3.4 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.22 (d, J=2.1 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 3.27 (t, J=6.2 Hz, 2H), 2.66 (dd, J=15.1, 7.5 Hz, 1H), 2.54 (d, J=3.4 Hz, 3H), 1.46 (s, 9H), 1.27 (t, J=7.7 Hz, 3H), 1.19 (m, 2H), 0.50 (t, J=7.4 Hz, 3H).
Reaction SMILES: [BH4-].[Li+].[CH2:3]([N:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][C@H:12]([F:17])[C:13](OC)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[CH2:18]([N:10]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:11][C@H:12]([F:17])[CH2:13][OH:14])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@@H](F)CN(Cc1ccccc1)Cc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC[C@@H](F)CN(Cc1ccccc1)Cc1ccccc1
Temperature: -15 °C
Yield: 92.4 %

Procedure:
Lithium borohydride (17.7 g, 0.81 mol) was suspended in THF (400 mL) under a nitrogen atmosphere and cooled to −15° C. with stirring. Methyl (2S)-3-(dibenzylamino)-2-fluoropropanoate (188.3 g, 0.62 mol) was suspended in THF (400 mL) and added dropwise to the mixture. On completion of addition, the reaction mixture was allowed to warm to room temperature and stirred at this temperature for 3 h. TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to 0° C. and cautiously quenched with a saturated aqueous solution of ammonium chloride (300 mL). Additional water (400 mL) was added then the reaction mixture was extracted with ethyl acetate and the organic phase was concentrated under reduced pressure. The crude residue was dissolved in 2 N hydrochloric acid and the aqueous phase was washed twice with ether. The aqueous phase was basified (pH=10 approx.) with 80% ammonium hydroxide in brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (2S)-3-(dibenzylamino)-2-fluoro-1-propanol (156.6 g, 92%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.15–7.38 (m, 10H), 4.65–4.78 (m, 0.5H), 4.48–4.58 (m, 0.5H), 3.50–3.82 (m, 6H), 2.70–2.88 (m, 2H).
Reaction SMILES: [CH2:1]1[CH2:20][O:19][C:3]2([CH2:8][CH2:7][C:6](O)([C:9]3[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[CH:10]=3)[CH2:5][CH2:4]2)[O:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:20]1[CH2:1][O:2][C:3]2([CH2:8][CH2:7][C:6]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[CH:10]=3)=[CH:5][CH2:4]2)[O:19]1
Reactant: OC1(c2cc(F)c(F)c(F)c2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1cc(C2=CCC3(CC2)OCCO3)cc(F)c1F
Yield: 65.8 %

Procedure:
1,1-Ethylenedioxy-4-hydroxy-4-(3',4',5'-trifluoro-phenyl)cyclohexane (166.2 g) was dissolved in toluene (500 ml), followed by adding p-toluenesulfonic acidmonohydrate (20 g) into the solution, stirring the mixture under reflux for one hour, washing the reaction solution with water (500 ml), drying the organic layer over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure, to obtain 1,1-ethylenedioxy-4-(3',4',5'-trifluorophenyl)-3-cyclohexene (102.6 g).