Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=4)[CH:9]=[C:10]([CH:11]3[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[ClH:41]>CO.O1CCOCC1>[ClH:41].[NH:14]1[CH2:15][CH2:16][CH2:17][CH:11]([C:10]2[N:6]3[C:7]([C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=4)[CH:9]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ncnn2c(C3CCCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]azepane-1-carboxylate in MeOH (10 mL) was added 4M HCl in dioxane (5 mL). The mixture was stirred at rt for 5 h. The mixture was concentrated to dryness to afford 924 mg (100%) of the desired product, which contained trace impurities. LC-MS [M+H]+=438.28, RT=2.10 min.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](=S)[NH2:7].O.[NH2:19][NH2:20].[CH:21](O)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]2[N:7]=[CH:21][NH:20][N:19]=2)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: NC(=S)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=CO
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cc(-c2nc[nH]n2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)benzothioamide (1) (205.65 g) in DMF (1.03 L) was treated with hydrazine hydrate (73.16 mL, 2.0 eq). The reaction mixture was stirred at ambient temperature for 1 h. before being treated with formic acid (1.03 L). The reaction mixture was refluxed at 90° C. for 2-3 h then allowed to cool down to ambient temperature, poured into saturated aqueous sodium bicarbonate (7 L) and extracted with EtOAc (3×1 L), The combined organic layers were washed with brine (3×500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 180 g of crude compound. This crude material was washed with petroleum ether (3×500 mL), filtered and dried well to afford 160 grams (75% yield) of triazole (2) obtained as a pale yellow solid.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[CH:10][C:11]([F:15])=[C:12]([OH:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[C:23]([Si:27]([CH3:29])([CH3:28])[O:14][C:12]1[CH:13]=[C:8]([C:7]([CH3:17])([CH3:16])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=[CH:10][C:11]=1[F:15])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(F)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.8 %

Procedure:
To a solution of 5-(tert-butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol (4.60 g, 17.9 mmol, 1.0 equiv) in anhydrous DMF (20 mL) at 0° C. under Ar was added imidazole (1.34 g, 19.7 mmol, 1.1 equiv) and tert-butyl-chloro-dimethyl-silane (2.97 g, 19.7 mmol, 1.1 equiv). After the addition was completed the cooling bath was removed and the reaction stirred for 18 h at rt. The reaction mixture was poured on ice, extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with a sat. solution of Na2CO3 (2×100 mL) and a sat. solution of NaCl (2×100 mL). The organic phase was dried over Na2SO4 and concentrated by evaporation under reduced pressure yielding 4.50 g (68%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 0.00 (s, 6H), 0.10 (s, 6H), 0.85 (s, 9H), 0.92 (s, 9H), 4.55 (s, 2H), 6.71-6.74 (m, 1H), 6.80-6.83 (m, 1H), 6.87-6.92 (m, 1H). MS (EI): 370.2 [M]+.
Reaction SMILES: FC1C=[C:8]([O:10]C)C=C(F)C=1CN.C([N:16](CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[F:41][C:42]1[CH:71]=[C:70]([O:72][CH3:73])[CH:69]=[C:68]([F:74])[C:43]=1[CH2:44][N:45]1[C:50]2[N:51]=[CH:52][CH:53]=[CH:54][C:49]=2[S:48](=[O:56])(=[O:55])[N:47]([C:57]2[CH:62]=[CH:61]C(OC)=[C:59]([O:65][CH3:66])[CH:58]=2)[C:46]1=[O:67]>CN(C=O)C>[F:74][C:68]1[CH:69]=[C:70]([O:72][CH3:73])[CH:71]=[C:42]([F:41])[C:43]=1[CH2:44][N:45]1[C:50]2[N:51]=[CH:52][CH:53]=[CH:54][C:49]=2[S:48](=[O:56])(=[O:55])[N:47]([C:57]2[CH:62]=[C:61]([O:10][CH3:8])[N:16]=[C:59]([O:65][CH3:66])[CH:58]=2)[C:46]1=[O:67]
Reactant: COc1cc(F)c(CN)c(F)c1
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(F)c(CN2C(=O)N(c3cc(OC)nc(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1

Procedure:
The title compound (108 mg, 0.22 mmol) was prepared in two steps from (IntC2) (165 mg, 0.5 mmol), 2,6-difluoro-4-methoxybenzylamine (90 uL, 0.6 mmol) and N,N-diisopropylethylamine (180 uL, 1.0 mmol); followed by 1,1′-carbonyldiimidazole (246 mg, 1.52 mmol), triethylamine (0.10 mL, 0.72 mmol) in DMF (1.5 mL) using the methods of (95).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2)C=[C:15]1C(OCC)=O>>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Product: COC(=O)c1ccc2ccn(C)c2c1
Yield: 95 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting methyl indole-6-carboxylate for the ethyl indole-2-carboxylate, the title compound (2.5 g, 95%) was obtained as white solid: MS (ES) m/e 190.2 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.ClCCl.Cl.ClCCl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:4]1(/[CH:3]=[CH:2]/[C:1]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:1](=[O:10])/[CH:2]=[CH:3]/[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:15][CH:14]=2)=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(/C=C/c1ccccc1)Nc1ccc(OC(=O)/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Cinnamoyl chloride (16.79 g, 100.8 mmoL) was added to a solution of 4-aminophenol (5.00 g, 45.8 mmol) and DMAP (0.56 g, 4.58 mmol) in pyridine (50 mL). The reaction mixture was stirred at room temperature for 30 min whereupon a solid mass formed. Dichloromethane (50 mL) was added and the resultant suspension was stirred at room temperature for 2 h. The reaction mixture was poured into 10% hydrochloric acid/dichloromethane and shaken. The precipitated white solid was removed by filtration, washed with dichloromethane, 10% hydrochloric acid and then dichloromethane again. The organic layer of the filtrate was separated and washed with 10% hydrochloric acid (×2) and brine, dried (Na2SO4) and evaporated to give the title compound (15.1 g, 89%). 1HNMR (300 MHz) (CDCl3) δ 6.55 (1H, d, J=16 Hz), 6.64 (1H, d, J=16 Hz), 7.18 (2H, d), 7.35-7.45 (6H, m), 7.58 (4H, m), 7.67 (2H, m), 7.78 (1H, d, J=16) and 7.88 (1H, d, J=16).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH3:19])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CCI
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)cc1C=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In DMF (150 ml) was dissolved 5-bromosalicylaldehyde (18.6 g). To the mixture was added at room temperature potassium carbonate (16.6 g) and then was added iodoethane (17.3 ml), and the mixture was stirred at 90° C. for 3 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 5-bromo-2-ethoxybenzaldehyde (17.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:26]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1.[BH4-].[Na+].CC(C)=O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C@H:26]2[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1
Reactant: CC(C)c1nnc2ccc(-c3sc(C4CCC(=O)CC4)nc3-c3ccc(F)cc3F)nn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: CC(C)c1nnc2ccc(-c3sc([C@H]4CC[C@H](O)CC4)nc3-c3ccc(F)cc3F)nn12
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
The 4-(4-(2,4-difluorophenyl)-5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiazol-2-yl)cyclohexanone (0.495 g, 1.09 mmol) was dissolved in MeOH (5 mL) then cooled to about −5° C. Sodium borohydride (0.041 g, 1.09 mmol) was added and the mixture was stirred for about 5 min. Acetone was added, the solvents were concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel with DCM/MeOH (95:5) as an eluent then by RP-HPLC (Table 1, Method f) to give the title compound (0.209 g, 42%): LC/MS (Table 1, Method a) Rt=2.29 min; MS m/z: 456.2 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([NH:14][OH:15])([CH3:13])([CH3:12])[CH3:11]>Cl.C(Cl)(Cl)Cl>[C:10]([N+:14]([O-:15])=[CH:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: O=CCc1ccccc1
Reactant: CC(C)(C)NO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[N+]([O-])=CCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a mixture of phenyl-acetaldehyde (1.20 g, 10.00 mmol) and chloroform (50 ml) was added N-tert-butylhydroxylamine (1.07 g, 12.00 mmol) followed by 5 drops of conc. HCl. The mixture was stirred at rt for 18 h. The mixture was concentrated under vacuum to give an oil. The residue was purified by column chromatography (hexane:EtOAc=1:1) followed by EtOAc to give the title compound as a white solid: Yield: 80%, m.p. 143° C.: 1H NMR (CDCl3) δ 7.38 (m, 5H), 6.90 (s, 1H), 4.95 (dd, 2H), 1.25 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>>[F:10][C:9]([F:12])([F:11])[C:8]([Cl:17])=[N:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(NCc1ccc(Cl)cc1)C(F)(F)F
Product: FC(F)(F)C(Cl)=NCc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A mixture N-(p-chlorobenzyl)-2,2,2-trifluoroacetamide (100.0 g, 0.421 mol) and phosphorus pentachloride (87.7 g, 0.421 mol) is heated to 100° C., stirred for two hours and vacuum distilled to obtain the title product as a clear colorless liquid (66.3 g, bp 110°-112° C./7.5 mm Hg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:24][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To the above ethyl (S)-4-(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxybenzoate was added MeOH (100 mL) and 1 N NaOH (50 mL). The mixture was stirred for 15 hr at room temp. After removal of MeOH under a reduced pressure, water (50 mL) was added to the residual solution. The aqueous solution was washed with Et2O (×2) and then acidified by the addition of 1 N HCl. The mixture was extracted with EtOAc., washed with water, brine, dried over MgSO4 and evaporated in vacuo to afford 4.26 g (95%) (S)-4-(1-tert-butoxycarbonyl-2-pyrrolidinyl) methoxybenzoic acid as a crystalline solid.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:28](=[O:29])[C:27]([OH:26])([CH3:32])[CH3:31])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CC(C)(O)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CC(C)(O)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (12.3 mg, 42.2%), MS (ISP) m/z=417.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and 2-hydroxy-2-methylpropanoic acid
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1F
Product: Fc1cc(Br)ccc1OCc1ccccc1
Yield: 99.4 %

Procedure:
Analogously to the synthesis described above (under Example 2.1 or 872.1), 250 g (1.31 mol) of 4-bromo-2-fluorophenol and 179 ml (1.51 mol) of benzyl bromide gave 366 g (97%) of 1-benzyloxy-4-bromo-2-fluorobenzene as colourless crystals.
Reaction SMILES: C1(O)C=CC=CC=1.II.ClC1C(Cl)=C(C=CC=1)N(Cl)Cl.Cl[C:22]1[C:27]([NH2:28])=[C:26](Cl)[C:25]([Cl:30])=[C:24](Cl)[C:23]=1[Cl:32].[H][H]>O.[Ta]>[Cl:30][C:25]1[CH:26]=[C:27]([CH:22]=[C:23]([Cl:32])[CH:24]=1)[NH2:28]
Reactant: [H][H]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Ta]
Agent: Clc1cccc(N(Cl)Cl)c1Cl
Agent: II
Solvent: O
Solvent: Oc1ccccc1
Product: Nc1cc(Cl)cc(Cl)c1
Yield: 94 %

Procedure:
200 parts of phenol, 5.7 parts of iodine, 197 parts of a tetrachloroaniline/pentachloroaniline mixture according to the data in Example 3, and 20 parts of ruthenium-on-charcoal catalyst (5% strength) are subjected to a hydrogenating dehalogenation in a tantalum autoclave at 175° C. with hydrogen under a maximum pressure of 50 bars. In the working up process, the hot mixture is dissolved in 450 parts by volume of water at 100° C., the catalyst is separated off through a suction filter and the filtrate is neutralised with sodium hydroxide solution. 3,5-Dichloroaniline and phenol are separated off from the water phase with the aid of toluene, and the organic solution is distilled. After distilling off toluene and water, the phenol is separated off from the 3,5-dichloroaniline by distillation and can be used again. The crude 3,5-dichloroaniline which remains is purified by distillation over a simple distillation bridge. 132 parts of 98% strength 3,5-dichloroaniline is obtained; yield 94% of theory.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][C:5]([C:13]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1Br.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[C:3]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)=[CH:4][C:5]([C:13]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]2)=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: CCOC(=O)C1(c2cc(Br)c(N)c(OCC3CC3)c2)CCC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C1(c2cc(OCC3CC3)c(N)c(-c3ccc(C(F)(F)F)cc3)c2)CCC1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mixture of ethyl 1-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (0.32 g, 0.86 mmol), 4-trifluoromethylphenylboronic acid (0.246 g, 1.3 mmol), CsF (0.262 g, 1.7 mmol) and Pd (PPh3)4 (0.1 g, 0.08 mmol) in 10 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled to RT and 25 mL of EtOAc and 75 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 1-(6-amino-5-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)cyclobutanecarboxylate (0.290 g) as a yellow oil.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1>ClCCl>[Br:1][CH2:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)=[O:12]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: BrBr
Solvent: ClCCl
Product: O=C(CBr)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 86.3 %

Procedure:
Bromine (80 g, 500 mmol) was added dropwise to a solution of 1-(4-bromo-phenyl)-ethanone (100 g, 500 mmol) in dichloromethane (1500 mL) at ambient temperature. The reaction mixture was stirred for 3 h and then concentrated. The residue was washed with dichloromethane (100 mL) to give the crude title compound (120 g, 86% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.78 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 4.32 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][CH3:20])[C:4]([CH2:3][CH2:2][NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=3)=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCNC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under a nitrogen atmosphere, a solution of 1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.250 g, 0.928 mmol), triethylamine (0.30 g, 3.0 mmol), and 4-fluorobenzoyl chloride (0.18 g, 1.1 mmol) in dichloromethane (7 mL) was stirred for two hours and then concentrated under reduced pressure. The residue was dissolved in methanol, and 1 N hydrochloric acid was added. The reaction was stirred for three days at room temperature and then heated at reflux overnight. A precipitate was present and was isolated by filtration and stirred with 2 M aqueous sodium carbonate. The resulting mixture was extracted with dichloromethane. The combined extracts were then concentrated under reduced pressure. The residue was purified by chromatography using an INTELLIFLASH system (eluting with 0% to 30% CMA in chloroform). The pure product was dried in a vacuum oven overnight at 90° C. to provide N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-4-fluorobenzamide as a white powder, mp 198-199° C.
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:20].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[CH3:1][C:6]([O:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:17])[C:10]=1[Cl:16])[C:7](=[O:18])[C:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)([CH3:19])[CH2:14]2)([CH3:14])[C:7]([OH:18])=[O:20]
Reactant: [OH-]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(C)(Oc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2)C(=O)O

Procedure:
To a refluxing solution of 2-cyclopentyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (15.5 g., 0.05 mole) in acetone (500 ml.) in an inert atmosphere is added solid sodium hydroxide (12.6 g., 0.25 mole). Chloroform (7.6 g., 0.69 mole) in acetone (50 ml.) is added dropwise during a 10-minute period. The reaction mixture is refluxed for 5 hours, then evaporated to dryness at reduced pressure. The residue is dissolved in water, filtered and acidified with hydrochloric acid and affording α,α-dimethyl-(1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(O)C=CC=CC=1.C(O)CC/C=C/CCCCC.[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]CCCCCCCC)=[CH:36][CH:35]=1>CCOCC>[CH3:31][O:32][C:33](=[O:59])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43]/[CH:44]=[CH:45]/[CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:36][CH:35]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Agent: CCCCC/C=C/CCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: CCCCC/C=C/CCCOc1ccc(C(=O)OC)cc1
Yield: 80 %

Procedure:
DEAD (641 mg, 3.68 mmol), phenol 34 (487 mg, 3.2 mmol), alcohol 26i (500 mg, 3.2 mmol), and TPP (966 mg, 3.68 -mmol) in 16 ml anhydrous ether were reacted according to the procedure for compound 35a. The crude product was purified via flash chromatography over silica gel with gradual elutions from 95/5 to 90/10 (v/v, Hex/EtOAc). Evaporation of the solvent yielded 748 mg (80%) of colorless liquid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])=[O:2].[CH3:13]O>>[CH3:13][O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([CH:1]=[O:2])[CH:4]=[CH:5][C:6]=1[OH:12]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: CO
Product: COC(=O)c1cc(C=O)ccc1O
Temperature: 25 °C
Yield: 79 %

Procedure:
Heat a mixture of 5-formyl-2-hydroxy-benzoic acid (5.0 g, 30.09 mmol) concentrated sulfuric acid (5 mL) in methanol (100 mL) at reflux for 24 h. Cool the mixture to room temperature and concentrate under reduced pressure. Purify the resulting residue by chromatography over silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as a colorless oil (4.28 g, 79%). 1H NMR (CDCl3, 300 MHz) δ 3.88 (s, 3H), 4.52 (bs, 1H), 7.05 (d, J=8.56 Hz, 1H), 7.84 (d, J=8.56 Hz, 1H), 8.40 (s, 1H), 9.85 (s, 1H); TLC Rf=0.34 (3:1 Hexanes/Ethyl Acetate).