Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:7]1[N:11]2[N:12]=[C:13]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[ClH:24]>C(O)C.[Pd].CCOCC>[ClH:24].[CH2:1]([C:7]1[N:11]2[N:12]=[C:13]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1cnc2ccc(NCc3ccccn3)nn12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCCCCCc1cnc2ccc(NCc3ccccn3)nn12
Reaction time: 24 h
Yield: 41 %

Procedure:
3-(Hex-1-ynyl)-N-(pyridin-2-ylmethyl)imidazo[1,2-b]pyridazin-6-amine was dissolved in ethanol (5 mL) with 5% palladium on charcoal and placed under hydrogen (50 psi) in a Parr shaker. After 24 hr, the reaction mixture was filtered through celite and concentrated to provide the free-base. This was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (26 mg, 41%) as an orange solid; 1H NMR (300 MHz, CD3OD) δ 8.52 (d, J=5.0 Hz, 1H), 7.92 (d, J=9.8 Hz, 1H), 7.89-7.83 (dt, J=1.7, 9.4 Hz, 1H), 7.63 (s, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.37-7.35 (m, 1H), 7.31 (d, J=9.8 Hz, 1H), 4.73 (s, 2H), 2.78 (t, J=7.4 Hz, 2H), 1.55-1.48 (m, 2H), 1.29-1.25 (m, 6H), 0.98 (t, J=6.6 Hz, 3H); 13C NMR (75 MHz, CD3OD) δ 158.2, 156.2, 148.8, 139.0, 132.9, 131.9, 123.6, 122.8, 121.0, 119.8, 118.2, 46.9, 32.0, 29.3, 27.1, 23.2, 23.0, 13.8; HPLC tR=9.26 min (Luna), 95.3%; ES-MS: (M+H)=310 m/z.
Reaction SMILES: [CH:1]12[N:9]([C:10]3[N:15]=[C:14]([C:16]4[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=4)[N:13]=[C:12]4[N:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:24]=[CH:25][C:11]=34)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][O:3][CH2:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.[N:45]([C:48]1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C(N3C4CCCC3COC4)N=2)=CC=1)=[C:46]=[O:47]>ClCCl.O1CCCC1.C(N(CC)CC)C>[CH:5]12[N:9]([C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([NH:20][C:46]([NH:45][CH3:48])=[O:47])=[CH:21][CH:22]=4)[N:13]=[C:12]4[N:23]([CH2:26][C:27]([F:29])([F:28])[F:30])[N:24]=[CH:25][C:11]=34)[CH:1]([CH2:8][CH2:7][CH2:6]1)[CH2:2][O:3][CH2:4]2
Reactant: Nc1ccc(-c2nc(N3C4CCCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: O=C=Nc1ccc(-c2nc(N3C4CCCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: CN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(-c2nc(N3C4CCCC3COC4)c3cnn(CC(F)(F)F)c3n2)cc1

Procedure:
A solution of 4-(4-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (50 mg, 0.12 mmol) in dichloromethane (3 mL) was treated triethylamine (160 μL), followed by triphosgene (27 mg, 0.09 mmol) as a solution in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 2.0 M methylamine solution in tetrahydrofuran (1.2 mL)—was added to the 9-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-9-azabicyclo[3.3.1]nonane (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 1-(4-(4-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-methylurea. MS (ES+): 476.3 (M+H)+
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C@@H:6]1[C@@H:13]([OH:14])[C@H:12]([CH3:15])[O:11][C@@H:8]([O:9]C)[CH2:7]1)=[O:4].[N+](=[CH2:20])=[N-].B(F)(F)F>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:20][O:14][C@H:13]1[C@H:12]([CH3:15])[O:11][CH:8]([OH:9])[CH2:7][C@@H:6]1[NH:5][C:3](=[O:4])[C:2]([F:17])([F:16])[F:1]
Reactant: C=[N+]=[N-]
Reactant: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@@H](O)[C@H](C)O1
Agent: FB(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CO[C@@H]1[C@@H](NC(=O)C(F)(F)F)CC(O)O[C@H]1C
Yield: 98 %

Procedure:
Treatment of 2.57 g; 10 mmoles of methyl 2,3,6-trideoxy-3-trifluoroacetamido-α-L-arabino-hexopyranoside (III-A) in methylene dichloride with diazomethane/boron-trifluoride, as described in Example I gave the corresponding 4-O-methylderivative (III-B, 1.7 g., 63%): m.p. 185°; [α]D23° =-101° (c=1, in CHCl3); mass spectrum m/e 271 (H+); pmr spectrum (CDCl3); 1.31 (d, CH3 --C--5), 3.30 and 3.43 (two s, OCH3) and 4.70δ (broad s, C--1--H). Acid hydrolysis of compound III-B as in Example I (1.63 g., 6 mmoles) gave 2,3,6-trideoxy-4-O-methyl-3-trifluoroacetamido-L-arabino-hexopyranose (III-C, 1.51 g., 98%): m.p. 201°; [α]D23° =-12.7° (c=0.48, in CHCl3); mass spectrum m/e 257 (M+).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]=[C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]1)C.[OH-].[Na+]>CO.C1COCC1>[C:17]([O:16][C:14]([NH:13][CH2:12][CH:9]1[CH2:8][CH2:7][C:6](=[CH:5][C:4]([OH:21])=[O:3])[CH2:11][CH2:10]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C=C1CCC(CNC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CCC(=CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 64 %

Procedure:
To a solution of [4-(tert-Butoxycarbonylamino-methyl)-cyclohexylidene]-acetic acid ethyl ester (0.518 g, 1.74 mmol) in MeOH (16 mL) and THF (4 mL) was added sodium hydroxide (9.0 mL, 1N, 9.0 mmol) and the reaction stirred at RT for 23 hr. The reaction was quenched with H2O and extracted with EtOAc (2×). The aqueous layer was acidified to pH 1 with 1N HCl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide 0.300 g (64%) of product. ESI-MS m/z 270 (MH)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=O)[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[C:18]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[F:16])=[CH:21][CH:20]=1)#[N:17]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC)cc1F

Procedure:
(RS)-Ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Yellow oil. MS 343.2 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH:19]([S:22]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][N:26]=1)(=[O:24])=[O:23])([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH2:9][N:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]([S:22]([CH:19]([CH3:21])[CH3:20])(=[O:23])=[O:24])=[N:26]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)S(=O)(=O)c1n[nH]c2ccccc12
Reactant: CS(=O)(=O)CCn1c(CCl)nc2cc(Cl)ccc21
Product: CC(C)S(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CCS(C)(=O)=O)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 1-9 by using 5-chloro-2-(chloromethyl)-1-(2-(methylsulfonyl)ethyl)-1H-benzo[d]imidazole and 3-(isopropylsulfonyl)-1H-indazole instead of 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole and 3-(isopropylsulfonyl)-1H-indazole.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH2:13][C:12]3[S:11][C:10]([C:16]([NH2:18])=[O:17])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[C:19]([C:21]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>>[OH:26][C:21]1([C:19]#[C:20][C:2]2[CH:3]=[CH:4][C:5]3[O:15][CH2:14][CH2:13][C:12]4[S:11][C:10]([C:16]([NH2:18])=[O:17])=[N:9][C:8]=4[C:6]=3[CH:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: C#CC1(O)CCCC1
Product: NC(=O)c1nc2c(s1)CCOc1ccc(C#CC3(O)CCCC3)cc1-2

Procedure:
9-Bromo-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide (0.15 g) was reacted with 1-ethynylcyclopentanol similar to as described in Procedure E to afford 46.2 mg of 9-[2-(1-hydroxycyclopentyl)ethynyl]-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide following reverse phase hplc purification. MS (Q1) 355 (M)+. 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=2.1 Hz, 1H), 8.40 (s, 1H), 7.84 (s, 1H), 7.27 (dd, J=8.3, 2.1 Hz, 1H), 7.01 (t, J=7.6 Hz, 1H), 5.26 (s, 1H), 4.34 (t, J=4.9 Hz, 2H), 3.41 (t, J=4.9 Hz, 2H), 2.00-1.82 (m, 4H), 1.82-1.59 (m, 5H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([Cl:15])[N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19]>C(N(CC)CC)C>[CH2:1]([C:5]1[N:6]=[C:7]([Cl:15])[C:8]([N+:12]([O-:14])=[O:13])=[C:9]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCC(N)CC
Reactant: CCCCc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Product: CCCCc1nc(Cl)c([N+](=O)[O-])c(NC(CC)CC)n1
Reaction time: 3 h

Procedure:
200 ml of alcohol and 4.5 g (44 m-moles) of triethylamine are added to 11 g (44 m-moles) of 2-n-butyl-4,6-dichloro-5-nitro-pyrimidine. At -50° C, 4.0 g (44 m-moles of 3-aminopentane are added dropwise. The reaction mixture is stirred for 3 hours and then evaporated. The residue is suspended in 100 ml of water and extraction is performed with ether. The ethereal extracts are dried over MgSO4 and evaporated to yield 10.5 g of 2-n-butyl-4-chloro-5-nitro-6-(3-pentylamino)-pyrimidine (nD20 : 1.5383) as a yellow oil
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[C:7]3[C:12]([CH2:13][S:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.C(O)(=[O:20])C>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[O:15])[C:7]3[C:12]([CH2:13][S:14](=[O:20])[C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: CC(=O)O
Reactant: O=C1c2ccc(Cl)cc2SCc2cccnc21
Product: O=C1c2ccc(Cl)cc2S(=O)Cc2cccnc21
Reaction time: 7 h

Procedure:
A solution of 8-chloro-5,11-dihydro[1]benzothiepino[4,3-b]pyridin-11-one (250 mg) in acetic acid (5 ml) was stirred for 5 minutes. NaBO3 (105 mg) was added and the mixture was stirred for 7 hours. The reaction was quenched with 5% NaOH and extracted with CH2Cl2, and the extracts were washed with brine, dried (MgSO4), filtered and concentrated to afford a tan solid (270 mg). This was chromatographed on silica to afford the crude sulfoxide (250 mg) as a tan solid containing some starting material; MS (CI, M+H)=278.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:31])([F:30])[CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O.[H-].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:18][C:17]([F:31])([F:30])[F:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(OCc2ccccc2)cc1
Temperature: 110 °C

Procedure:
To a solution of 4-benzyloxyphenol (5 g) and 2,2,2-trifluoroethyl-p-toluenesulphonate (5 g) in dimethylformamide (50 ml) was added sodium hydride (60% dispersion in oil, 2.3 g) and the solution heated to 110° C. for 16 h. The mixture was cooled, diluted with water and the product extracted into ethyl acetate. The organic phase was washed with water, brine and dried (MgSO4). The solvent was remove in vacuo and the residue chromatographed on silica gel (eluting with 10% diethyl ether/hexane) to give the the title compound as a solid, m.p. 72-74° C.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11](=[CH2:15])[CH2:12][CH2:13][OH:14])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].CN(C1C=CC=CN=1)C>ClCCl>[CH2:6]([O:5][P:4](/[CH:9]=[CH:10]/[C:11](=[CH2:15])[CH2:12][CH2:13][O:14][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: C=C(/C=C/P(=O)(OCC)OCC)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(/C=C/P(=O)(OCC)OCC)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A mixture of E-5-hydroxy-3-methylidene-1-pentenyl-phosphonic acid diethyl ester (1.07 g, 4.6 mmol), triethylamine (0.7 ml, 5 mmol), tosylchloride (0.96 g, 5 mmol) and dimethylaminopyridine (0.005 g, 0.04 mmol) in anhydrous and dichloromethane is stirred 4 hours at 20° C., concentrated in vacuo and the title product is obtained by flash chromatography on silica gel (1.55 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:15]([OH:17])=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[I:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:15](=[O:17])[NH:44][C:43]2[CH:45]=[CH:46][C:40]([I:39])=[CH:41][CH:42]=2)=[CH:9][CH:8]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Nc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(C(=O)O)c2ccc(C(C)(C)C)cc2)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(NC(C(=O)Nc2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
(4-{[(4-tert-Butyl-phenyl)-carb oxy-methyl]-amino}-benzoic acid tert-butyl ester (760 mg, 2.0 mmol), was taken up in 5 mL of DMF followed by addition of HOBt (765 mg, 5.0 mmol) and EDCT (958 mg, 5.0 mmol). The reaction was stirred at RT for 30 min, 4-iodoaniline (657 mg, 3 mmol) was added followed by Hunig's base (640 mg, 5 mmol) and allowed to stir an additional 16 h at RT. Ethyl acetate (20 mL) and 20 mL water were added and separated. The aqueous layer was then back extracted with another 10 mL of EtOAc, the organic layer were combined and washed with water (3×20 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give a brown solid. The solids were triturated with methanol to give a white solid (818 mg, 70%). 1H NMR (CDCl3): δ 1.32 (9H, s), 1.58 (9H, s), 4.89 (2H, d), 5.02 (1H, d), 6.62 (2H, d, J=8.4 Hz), 7.22-7.95 (10H, m), 8.81 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[C:9]([C:12](=[O:14])[CH3:13])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[CH:4]([CH3:18])[CH2:3]1.[Br:20]Br>C(O)(=O)C>[CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([CH3:15])=[C:9]([C:12](=[O:14])[CH2:13][Br:20])[CH:10]=2)[C:5]([CH3:17])([CH3:16])[CH:4]([CH3:18])[CH2:3]1
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)C(C)CC2(C)C
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc2c(cc1C(=O)CBr)C(C)(C)CC(C)C2(C)C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
1,1,3,4,4,6-Hexamethyl-7-acetyl-1,2,3,4-tetrahydronaphthalene (33 gm,0.12 m) was dissolved in glacial acetic acid (40 ml.) and the solution treated portionwise with bromine (20.3 gm) with stirring. The mixture was allowed to stand overnight at room temperature and poured onto ice (100 gm.). The resulting mixture was extracted with ether (3 ×100 ml.) and the combined extracts washed with saturated sodium carbonate (2 × 50 ml.) and then brine. The washed extracts were then dried (MgSO4) and the solvent removed in vacuo to give a crystalline solid. This was recrystallised from absolute ethanol to give 1,1,3,4,4,6-hexamethyl-7-bromoacetyl-1,2,3,4-tetrahydronaphthalene as colourless needles (16 gm, 38%) m.p. 68°C. [Found: C, 64.40; H, 7.65%. C18H25BrO requires: C,64.09; H,7.47%].
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:31](=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([O:21][CH3:31])=[CH:14][CH:13]=1)=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: COc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1C(N)=O

Procedure:
5-(N,N-Dibenzylglycyl)salicylamide (37.4 g) was heated at reflux for 2 hours with methyl iodide (10 ml) and anhydrous potassium carbonate (20 g) in ethyl methyl ketone (350 ml). The inorganic salts were filtered off and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water and again evaporated. The residual oil was crystallised from isopropanol to give 5-(N,N-dibenzylglycyl)-o-anisamide as a white solid, (14 g) m.p. 113°-114° .
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][NH:9][C:10](=[O:12])[O-:11].Br[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:7]([O:12][C:10]([NH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:15]=[CH:14][CH:13]=1)[O:4][C:3]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=1[NH:1][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:11])([CH3:13])([CH3:8])[CH3:6]
Reactant: Nc1ccc(Cl)cc1Oc1cccc(CNC(=O)[O-])c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 118.4 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzylcarbamate (3.5 g, 10 mmols), ethyl 4-bromobutyrate (2.9 ml, 20 mmols), potassium carbonate (1.4 g, 10 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 3 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminobutyrate (2.74 g, 59.3%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].N12CCCN=C1CCCCC2.Br[CH2:21][C:22](=[O:25])[CH2:23][CH3:24]>C1C=CC=CC=1>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([C:1]#[N:2])[CH2:21][C:22](=[O:25])[CH2:23][CH3:24])[CH3:8]
Reactant: CCOC(=O)CC#N
Reactant: CCC(=O)CBr
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(C#N)CC(=O)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a 5° C. solution containing 27.8 g (246 mmol) of ethyl cyanoacetate and 38.2 g (251 mmol) of 1,8-diazabicyclo[5.4.0]undec-7ene in 420 mL of benzene was added over 30 minutes a solution of 1-bromo-2-butanone in 70 mL of benzene. The ice bath was removed and the reaction stirred for 1 hour at ambient temperature. At this time, the solids were removed by filtration and washed with 100 mL of methyl tert-butyl ether. The filtrate and the wash were combined and concentrated. The crude product was purified by short path distillation (0.2 torr, 140° C.) to provide 40.0 g (88.9%) of 2-cyano-4-oxohexanoic acid ethyl ester as a colorless oil. nmr (500 MHz, CDCl3) δ1.09 (t, J=7.3 Hz, 3H), 1.31 (t, J=7.1 Hz, 3H), 2.50 (q, J=7.3 Hz, 2H), 2.96 (dd, J=5.5, 18.0 Hz, 1H), 3.16 (dd, J=7.2, 18.0 Hz, 1H), 3.96 (dd, J=5.5, 7.2 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([C:13]([CH3:15])=[O:14])=[CH2:12]>CC#N.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:12][CH2:11][C:13](=[O:14])[CH3:15]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: C=CC(C)=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: CC(=O)CCc1c[nH]c2ccc(F)cc12
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A solution of 5-fluoroindole (10.5 g, 78 mmol) in MeCN (150 mL) at 0° C. is treated with methyl vinyl ketone (9.5 mL, 117 mmol) and Sc(OTf)3 (383 mg, 0.78 mmol) and stirred for 1 h. The mixture is then stirred an additional 6 h at rt. The mixture is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10%-50% EtOAc in heptane to afford 4-(5-fluoro-1H-indol-3-yl)-butan-2-one (11.1 g, 70%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[C:7]([Cl:20])[C:6]=1[CH3:21])(=[O:3])[CH3:2].[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>>[C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[CH:15][CH:14]=2)=[C:7]([Cl:20])[C:6]=1[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CC(=O)Oc1cc(Cl)c(Oc2ccc(N)cc2)c(Cl)c1C
Product: CC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)C(C)C)cc2)c(Cl)c1C
Yield: 88.3 %

Procedure:
Methyl[3,5-dichloro-4-(4-aminophenoxy)phenyl] acetate (33 mg, 0.10 mmol), was coupled with isobutyryl chloride (11 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether), 35 mg (95%) of methyl-[3,5-dichloro-4-(4-isobutyramidophenoxy)phenyl] acetate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 30 mg (89%) of 3,5-dichloro-4-(4-isobutyramidophenoxy)phenylacetic acid.
Reaction SMILES: I[C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH2:18])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[CH3:15][N:14]1[C:5]2[C:4]3[N:3]=[C:2]([NH:26][CH:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)[N:11]=[CH:10][C:9]=3[CH2:8][CH2:7][C:6]=2[C:12]([C:16]([NH2:18])=[O:17])=[N:13]1
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(I)ncc1CC2
Reactant: CN1CCC(N)CC1
Product: CN1CCC(Nc2ncc3c(n2)-c2c(c(C(N)=O)nn2C)CC3)CC1
Yield: 0 %

Procedure:
8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (0.10 g, 0.28 mmol) and 1-methylpiperidin-4-amine (0.19 g, 1.7 mmol) were heated at 80° C. under nitrogen for 3 hours. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on a silica gel column (eluant: dichloromethane/ethanol/ammonium hydroxide 90/10/1) to give 0.047 mg of 1-methyl-8-[(1-methylpiperidin-4-yl)amino]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (50% yield).
Reaction SMILES: [CH3:1][C:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[N:20][C:21]4[N:22]([N:31]=[CH:32][C:33]=4[C:34](O)=[O:35])[C:23]=3[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:17])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:19]=[N:20][C:21]4[N:22]([N:31]=[CH:32][C:33]=4[C:34]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:35])[C:23]=3[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:17])[CH2:14][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: CCS(N)(=O)=O
Reactant: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)O)cnn3c1Nc1ccccc1)CC2
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3)c(C(=O)N3CCC4(CC3)C(C)=Cc3ccccc34)cnc12
Yield: 63.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-(2-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)-7-phenylaminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.090 g, 0.188 mmol) obtained in Example 114, step 4 and ethanesulfonamide (0.102 g, 0.939 mmol), the title compound (0.068 g, 63%) was obtained.