Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7](C(=O)C(F)(F)F)[CH2:6][CH2:5]2.O.O.[NH4+].[CH3:21][N:22]1C(=O)CCC1>>[CH2:8]1[C:9]2[C:4](=[CH:3][C:2]([C:21]#[N:22])=[CH:11][CH:10]=2)[CH2:5][CH2:6][NH:7]1
Reactant: CN1CCCC1=O
Reactant: O=C(N1CCc2cc(Br)ccc2C1)C(F)(F)F
Agent: [NH4+]
Solvent: O
Product: N#Cc1ccc2c(c1)CCNC2

Procedure:
The compound (2.23 g) obtained in Example 17-2 was dissolved in NMP (27 ml) and added with cuprous cyanide (1.56 g) and the whole was refluxed under heating for 4 hours. After completion of the reaction, the whole was cooled with ice and added with water and ammonium water. The resultant was subjected to extraction with chloroform and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The resultant was dissolved in diethyl ether and added with a 4 mol/l hydrogen chloride/dioxane solution. The precipitate was filtrated and washed with diethylether. The resultant was dried under heating, thereby obtaining a hydrochloride (1.95 g) of the subject compound as a brown solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[CH:10][N:11]=1)(=O)C.C([O-])([O-])=O.[K+].[K+].O.C(Cl)[Cl:23]>>[Cl:23][C:14]1[C:8]2[C:9](=[CH:10][N:11]=[C:6]([CH2:5][OH:4])[CH:7]=2)[O:12][CH:13]=1
Reactant: CC(=O)OCc1cc2ccoc2cn1
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCc1cc2c(Cl)coc2cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Furo[2,3-c]pyridin-5-ylmethyl acetate (956 mg, 5 mmol) is dissolved in CH2Cl2 (40 mL) and cooled to 0° C. Chlorine gas is bubbled through the solution for 15 min, the cooling bath is immediately removed and the mixture stirred for 2 h. The mixture is re-cooled to 0° C., saturated with chlorine gas, the cooling bath removed and the solution warmed to rt. The solution is layered with saturated NaHCO3 (20 mL), stirred gently for 2 h then stirred vigorously for 15 min. The mixture is diluted with saturated NaHCO3 (50 mL), extracted with CH2Cl2 (1×40 mL then 1×20 mL), dried over K2CO3 and concentrated to a volume of 20 mL under a stream of nitrogen. The solution is diluted with EtOH (35 mL), treated with K2CO3 (4.09 g, 29.6 mmol) and stirred for 18 h at rt. Water (7 mL) is added and the mixture stirred for 2 days. The mixture is concentrated to dryness, partitioned between 50% saturated NaCl (50 mL) and CH2Cl2 (4×50 mL), dried over K2CO3 and concentrated in vacuo to a brown solid (833 mg). The crude material is chromatographed over a standard 40 g Biotage column, eluting with 50% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 624 mg (68%) of (3-chlorofuro[2,3-c]pyridin-5-yl)methanol as a yellow oil. 1H NMR (DMSO-d6): δ 4.69, 5.56, 7.69, 8.55, 8.93 ppm.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15]2=[O:20].C(Cl)Cl.O=O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(N(CC)CC)C>[O:10]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15]2=[O:20])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCc2c(O)cccc21
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2c(Oc3ccccc3)cccc21
Yield: 72.7 %

Procedure:
To phenyl boronic acid (1.0 g) and 4-hydroxy-2,3-dihydro-1H-inden-1-one (1.0 g), methylene chloride (67 mL) was added and thereto, copper (II) acetate (1.4 g), molecular sieves 4A (1.9 g), and triethylamine (4.7 mL) were added, followed by stirring the resultant reaction mixture at room temperature in an oxygen atmosphere for 19 hours. The reaction mixture was filtered through a pad of Celite and the filtered substance was washed with ethyl acetate. To the resultant filtrate, a 1M aqueous solution of sodium hydroxide was added and the resultant mixture was filtered through a pad of Celite again. The resultant filtrate was phase-separated into an aqueous phase and an organic phase and the aqueous phase was extracted with ethyl acetate to combine the resultant organic phase with the above organic phase. The combined organic phase was washed with saturated saline and was dried over sodium sulfate anhydride. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain the subject compound (1.1 g) as an orange solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[Br:15][CH2:16][CH2:17]Br.[K+].[Br-]>>[Br-:15].[Br:15][CH2:16][CH2:17][C:1]1[C:14]2[C:5](=[NH+:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: BrCCBr
Agent: [Br-]
Agent: [K+]
Product: BrCCc1cccc2[nH+]cc3ccccc3c12
Temperature: 110 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
Phenanthridine (5.44 g; 30.4 mmol) was dissolved in 1,2-Dibromoethane (114.2 g; 52 ml; 608 mmol) and stirred at 110° C. for three days. During that time, a white precipitate was formed and was filtered off every 12 hours. After each filtration, the precipitate was rinsed with an additional 5 ml of 1,2-Dibromoethane and the mother liquor was stirred at 90° C. until the next filtration. The reaction was complete after ca. three days when no more precipitate formed. The filtrates were combined and washed thoroughly with ether and with ethyl acetate to give 2 (7.92 g; 21.6 mmol) as a beige powder in a 95% yield; mp: 234-235° C. (dec.); 1H NMR (D2O, 400 MHz): δ 9.81 (s, 1H), 8.72 (d, 1H, J=7.2 Hz), 8.63 (d, 1H, J=7.2 Hz), 8.37 (d, 1H, J=7.2 Hz), 8.26 (d, 1H, J=7.2 Hz), 8.18 (t, 1H, J=7.2 Hz), 7.98 (t, 1H, J=7.2 Hz), 7.90 (m, 2H), 5.37 (t, 2H, J=5.8 Hz), 4.05 (t, 2H, J=5.8 Hz); 13C NMR (D2O, 100 MHz): δ 155.27 (CH), 139.03 (CH), 135.59 (C), 133.18 (CH), 132.78 (C), 132.58 (CH), 130.85 (CH), 130.72 (CH), 126.57 (C), 125.13 (CH), 123.32 (C), 123.00 (CH), 118.91 (CH), 58.87 (CH2), 29.41 (CH2); IR (KBr, cm−1): 2947(w), 1620(m), 763(s), 717(m); MS (ES): 288.1 (M−Br) (100), 206.2 (8); Anal. Calcd for C15H13NBr2: C, 49.32; H, 3.59; N, 3.84. Found: C, 49.15; H, 3.48; N, 3.76.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([NH:12][C:13]([N:15]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17][CH2:16]2)=[O:14])([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:8][C:7]1[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3][C:4]([C:9]([NH:12][C:13]([N:15]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17][CH2:16]2)=[O:14])([CH3:11])[CH3:10])=[CH:5][CH:6]=1
Reactant: CC(C)(NC(=O)N1CCN2CCC1CC2)c1ccc(F)c(Br)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)N1CCN2CCC1CC2)c1ccc(F)c(-c2ccccc2)c1
Yield: 66.3 %

Procedure:
Using general procedure E, N-[2-(3-bromo-4-fluorophenyl)propan-2-yl]-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide (100 mg, 0.261 mmol), phenylboronic acid (79 mg, 0.65 mmol) and palladium (II) acetate gave the title compound as an off-white solid (66 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2H), 7.44-7.40 (m, 5H), 7.08(m, 1H), 4.78(br s, 1H), 4.00 (br s, 1H), 3.60 (m, 2H), 3.11-2.92 (m, 6H), 2.00 (m, 2H) 1.67(m, 7H), 1.26 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 159.6, 155.6, 144.6, 136.5, 129.3, 128.6, 128.5, 127.8, 127.5, 125.7, 125.6, 116.1, 115.9, 57.9, 55.3, 48.2, 46.4, 46.4, 41.6, 30.6, 30.5, 29.9, 27.6 ppm. Purity: >99% UPLCMS (210 nm); retention time 0.88 min; (M+1) 382.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:17]([OH:19])=O)=[C:8]([C:13]([F:16])([F:15])[F:14])[N:9]2[CH3:12])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:17]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH3:12])[C:8]=1[C:13]([F:16])([F:15])[F:14])=[O:19]
Reactant: CN
Reactant: COc1ccc2c(C(=O)O)c(C(F)(F)F)n(C)c2c1
Agent: O=C(Cl)C(=O)Cl
Product: CNC(=O)c1c(C(F)(F)F)n(C)c2cc(OC)ccc12
Yield: 98 %

Procedure:
This material was prepared from 6-methoxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic acid 76f (880 mg, 3.22 mmole), oxalyl chloride (3 ml, 2.0M solution) and methylamine (5 ml, 2.0M solution) in a manner as previously described for example 16d to give 900 mg product as white solid (98% yield). 1H NMR (300 MHz, CDCl3) δ7.62 (1H, d, J=8.9 Hz), 6.88 (1H, dd, J=2.1, 8.9 Hz), 6.73 (1H, d, J=2.1 Hz), 5.80 (1H, bs), 3.88 (3H, s), 3.79 (3H, s), 3.04 (3H, d, J=4.9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][C:17]([OH:19])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][C:17](=[O:19])[NH:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: NCc1ccccc1
Product: O=C(CC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)NCc1ccccc1
Yield: 49.5 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 8-bromo-5-carboxymethyl-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (130 mg, 0.40 mmol) and benzylamine (48 μL, 0.44 mmol) to give 82 mg of the title compound (51%): mp 252° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.13 (s, 1H), 8.69 (t, 1H, J=6 Hz), 7.18~7.34 (m, 5H), 7.20 (s, 2H), 5.16~5.22 (m, 1H), 4.27 (d, 2H, J=6 Hz), 2.80 (dm, 1H, J=18 Hz), 2.55 (dm, 1H, J=14 Hz), 2.46 (m, 1H, J=14 Hz), 1.87~2.03 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH2:6]O)[CH2:5][O:4][CH2:3]1.[OH-].[Na+].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O>C(Cl)Cl>[CH3:1][C:2]1([CH2:6][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:5][O:4][CH2:3]1
Reactant: CC1(CO)COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)CC2(C)COC2)cc1
Temperature: 0 °C

Procedure:
3-methyl-3-oxetanemethanol (100 g, 0.98 mol) was dissolved in 250 mL methylene chloride, and a 35% solution of sodium hydroxide (143.60 g, 1.08 mol)was added, and the reaction was cooled to 0° C. A solution of p-toluenesulfonyl chloride was added (186.67 g, 0.98 mol) in 375 mL methylene chloride was added over 1 hour. A white precipitate formed immediately. The reaction was stirred for 10 additional hours. 1000 mL of water was added. The dichloromethane solution layer was then removed, and dried with sodium sulfate, and the solvent was removed. Yield: 217.77 grams of 3-methyl-3-tosylmethyloxetane as white crystals, 87%.
Reaction SMILES: [CH2:1](O)[C@H:2]1[O:7][C@H:6]([O:8][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H:5](O)[C@@H:4]([OH:21])[C@@H:3]1O>O>[CH2:2]([O:7][C:6](=[O:8])[CH2:5][C@@H:4]([OH:21])[CH3:3])[CH3:1]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Product: CCOC(=O)C[C@H](C)O
Temperature: 30 °C

Procedure:
A slurry is made with 200 g fresh baker's yeast in a solution of 300 g saccharose in 1.6 l fresh water at 30° C., and this slurry is gently agitated at 30° C. After an hour, under strong agitation, 0.15 moles distilled acetoacetic ester are added, and the mixture is gently agitated for 24 hours at 25°-30° C. Subsequently, a solution of 200 g saccharose in 1 l water at 35 deg C. is added by portions. After strongly agitating for one hour, 0.15 moles acetoacetic ester are added once again. The mixture is agitated for 50 hours at 25°-30° C. Then it is suctioned over infusorial earth, and the residue is washed twice, each time with 100 ml water. The combined aqueous phases are saturated with NaCl and are extracted five times, each time with 500 ml ether. After separating and drying the organic phase over Na2SO4, it is concentrated by evaporation in a rotating evaporator down to 50-80 ml. Fractional distillation of the residue yields (S)-(+)-3-hydroxy-butyric acid ethyl ester in a yield amounting to 65-75 percent of theoretical.
Reaction SMILES: Cl[CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5]CC)=O.[OH:13][C:14]1[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>CCO>[CH2:11]([O:10][C:8]([CH:2]1[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[N:16][C:15]=2[NH:20][C:3]1=[O:5])=[O:9])[CH3:12]
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Reactant: Nc1ncccc1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1Oc2cccnc2NC1=O

Procedure:
Diethyl chloromalonate (9.73 g, 50 mmol) was added to a stirred mixture of 3-hydroxy-2-aminopyridine (5.51 g, 50 mmol), triethylamine (6.97 mL, 50 mmol) and EtOH (100 mL) at room temperature. The mixture was heated at reflux for 17 h and allowed to attain room temperature. The precipitate formed was filtered off, washed with EtOH and dried to give the product as a white solid: yield 3.85 g (35%); mp 160-162° C. Anal. (C10H10N2O4) C, H, N.
Reaction SMILES: [H-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[F:7][C:8]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:9]=1[C:10](OC1C=CC=CC=1)=[O:11].Cl>CCCCCC.CN(C)C=O>[N+:3]([CH2:6][C:10]([C:9]1[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:8]=1[F:7])=[O:11])([O-:5])=[O:4]
Reactant: C[N+](=O)[O-]
Reactant: O=C(Oc1ccccc1)c1cc(F)c(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(C[N+](=O)[O-])c1cc(F)c(F)cc1F
Temperature: 0 °C

Procedure:
Sodium hydride (12 g, 60% in oil, 297 mmol) was rinsed with hexane (4×100 mL), flushed with anhydrous nitrogen, suspended in N,N-dimethylformamide (350 mL) and then treated with nitromethane (44 mL, 81 mmol). The resultant mixture was stirred at room temperature for 2.5 hours, cooled to 0° C. and then treated with a solution of phenyl 2,4,5-trifluorobenzoate (22.8 g, 90.0 mmol) in N,N-dimethylformamide (180 mL) over a period of two hours. The reaction mixture was kept at the same temperature overnight and stirring continued for an additional hour at room temperature. The mixture was poured into ice (400 g) with conc. hydrochloric acid (48 mL). The aqueous mixture was extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was dissolved in ether-hexane (1:1, 240 mL) and water (200 mL). The organic layer was separated, and the crystals which formed upon standing and cooling in the freezer were recovered by filtration and dried to yield 2-nitro-1-(2,4,5-trifluorophenyl)ethanone as an off-white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:22])[CH:7]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[C:15]([CH3:21])[NH:16]2)[CH:8]([CH3:10])[CH3:9])[CH3:4].[Br:23][CH:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:5][C:6](=[O:22])[CH:7]([O:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[C:15]([CH3:21])[N:16]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][Br:23])[CH:8]([CH3:9])[CH3:10])[CH3:4]
Reactant: CCOC(=O)C(Oc1cccc2[nH]c(C)cc12)C(C)C
Reactant: CCCCCCCCCCCC(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cccc2c1cc(C)n2CCCCCCCCCCCCBr)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of NaH (60% in mineral oil, 0.42 g, 10 mmole) in anhydrous DMF (20 mL), 3-methyl-2-(2-methyl-1H-indol-4-yloxy)-butyric acid ethyl ester (2) (1.88 g, 7.0 mmole) and dibromododecane (2.30 g, 7.0 mmole) were added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (50 mL) and washed with water (3×30 mL). The organic layer was separated, dried over sodium sulphate and concentrated. The residue was purified by column chromatography (10:1 Hex:EtOAc) to afford intermediate (3) Yield: intermediate (3) 1.32 g, 35%, by-product (4) 1.56 g, 31%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:38].[OH-]>>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCCCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1nccc(-c2sc(C3CCCCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Yield: 57 %

Procedure:
Following a procedure analogous to Example 21 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-cyclohexyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.10 g, 0.177 mmol) and NH4OH (3 mL) the title compound was obtained (0.055 g, 57% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (br. s., 1H), 7.97 (br. s., 1H), 7.68 (br. s., 1H), 7.09-7.57 (m, 5H), 6.75 (br. s., 2H), 5.84 (br. s., 1H), 2.98 (d, J=0.5 Hz, 1H), 2.06 (br. s., 2H), 1.59-1.91 (m, 3H), 1.06-1.59 (m, 5H). m/z (ES+): 546 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][O:10][CH2:11][O:12][CH3:13].[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)#[N:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[CH:4][C:3]=1[CH2:9][O:10][CH2:11][O:12][CH3:13]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COCOCc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOCc1cc(OCc2ccc(C#N)cc2)ccc1Br
Temperature: 70 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A mixture of 4-bromo-3-(methoxymethoxymethyl)phenol (2.47 g, 10.0 mmol), 4-cyanobenzyl bromide (1.88 g, 9.50 mmol), and potassium carbonate (1.66 g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 70° C. for overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-[4-bromo-3-(methoxymethoxymethyl)phenoxymethyl]benzonitrile (1.88 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17](N)=[C:12]3[C:11]([CH3:20])=[CH:10]2)=[C:4]([CH3:21])[CH:3]=1.[OH:22]S(O)(=O)=O.N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[CH:16]=[C:17]([OH:22])[C:12]=3[C:11]([CH3:20])=[CH:10]2)=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(N)c2c(C)cn(-c3c(C)cc(Cl)cc3C)c2n1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(O)c2c(C)cn(-c3c(C)cc(Cl)cc3C)c2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
With ice-cooling, to a suspension of 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-ylamine (17.9 g) in a mixture of 1,4-dioxane (45 mL) and water (45 mL) was added dropwise a mixture of concentrated H2SO4 (17.8 mL) and water (90 mL) and then a solution of NaNO2 (6.2 g) in water (62 mL). The mixture was stirred at room temperature for 20 minutes, and heated at 100° C. for 1.5 hours. After cooling in an ice-cooling bath, the reaction mixture was poured into a cold saturated NaHCO3 aqueous solution and extracted with CHCl3. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a solid. The solid was washed with a mixture of ethyl acetate and diisopropylether (1:5) to give 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-ol (14.4 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:28])[CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH:13]=[N:12]2)=[C:5]([CH3:29])[CH:4]=1.[CH3:30][NH:31][CH3:32]>CN(C)C(=O)C>[CH3:30][N:31]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:28])[CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH:13]=[N:12]2)=[C:5]([CH3:29])[CH:4]=1)[CH3:32]
Reactant: CNC
Reactant: COc1ccc(COc2cnn(CC(=O)c3ccc(CBr)cc3C)c(=O)c2)nc1
Solvent: CC(=O)N(C)C
Product: COc1ccc(COc2cnn(CC(=O)c3ccc(CN(C)C)cc3C)c(=O)c2)nc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-5-(5-methoxy-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (preparation 9d, 120 mg, 0.26 mmol) in N,N-dimethylacetamide (2 mL) is added dimethylamine (0.76 mmol, 2 M solution in THF). The reaction mixture is stirred for 4 h at 40° C. The mixture is purified via reverse phase HPLC chromatography (Waters XBridge 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[C:29]3[CH3:37])[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:20])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[C:29]3[CH3:37])[CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)O)cnn3c1Nc1ccc(F)cc1)CC2
Product: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)NS(C)(=O)=O)cnn3c1Nc1ccc(F)cc1)CC2
Yield: 71.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluorophenylamino)-6-(2-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.040 g, 0.083 mmol) obtained in step 2 and methanesulfonamide (0.040 g, 0.417 mmol), the title compound (0.034 g, 71%) was obtained.
Reaction SMILES: C(#N)C.[CH3:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6].OI(C1C=CC=CC=1)[O:19][S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(OCC)(=O)C>[S:20]([O:22][CH2:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6])([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:21])=[O:19]
Reactant: CC(=O)c1ccc2ccccc2c1
Reactant: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC(=O)c2ccc3ccccc3c2)cc1
Yield: 68.5 %

Procedure:
Acetonitrile solution (40 mL) containing 2-acetonaphthone (1.70 g, 9.99 mmol) and [hydroxyl(tosyloxy)iodo]benzene (4.00 mg, 10.2 mmol) was heated under ref lux for 3 hours. The reaction mixture was cooled, and ethyl acetate was added thereto. The reaction solution was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to remove the solvent to obtain the title compound (2.33 g, 68.5%).