Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[N:8]1([C:4]2[N:3]=[C:2]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]4=[N:20][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Brc1cccc(N2CCCC2)n1
Product: FC(F)(F)c1ccn2c(-c3cccc(N4CCCC4)n3)cnc2n1
Yield: 26.8 %

Procedure:
2-Bromo-6-(pyrrolidin-1-yl)pyridine (481 mg, 2.1 mmol) (prepared by the method of T. Sammakia et al., J. Org. Chem., 1999, 64(13), 4652-4664) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to give 3-[6-(pyrrolidin-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (125 mg) as a white solid: δH (360 MHz, DMSO) 2.02 (4H, t, J 6.5), 3.51 (4H, bs), 6.43 (1H, d, J 8.4), 7.27 (1H, d, J 7.7), 7.63 (1H, t, J 7.9), 7.71 (1H, d, J 7.4), 8.72 (1H, s), 10.51 (1H, d, J 7.4); m/z (ES+) 334 (M++H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([CH:13]=O)=[CH:5][C:6]2[CH2:10][CH2:9][O:8][C:7]=2[C:11]=1[CH3:12].C(O)(=O)C>[Zn].O>[CH3:13][C:4]1[C:3]([CH3:2])=[C:11]([CH3:12])[C:7]2[O:8][CH2:9][CH2:10][C:6]=2[CH:5]=1
Reactant: Cc1c(C=O)cc2c(c1C)OCC2
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(c(C)c1C)OCC2
Reaction time: 12 h
Yield: 79 %

Procedure:
Zinc amalgum [prepared by heating a mixture of zinc dust (7.0 g), mercuric chloride (0.70 g), concentrated hydrochloric acid (0.5 ml) and water (30 ml) for 5 minutes and then decanting the aqueous solution] was added to a mixture of 2,3-dihydro-6,7-dimethylbenzo[b]furan-5-carboxaldehyde (6.93 g, 39 mmol), acetic acid (50 ml), water (50 ml), and concentrated hydrochloric acid (100 ml). The mixture was heated at reflux with vigorous stirring for 12 hours. After cooling, the mixture was poured into water. The dried (Na2SO4) ether extract was evaporated and the residue was purified by column chromatography over silica with hexane elution to give 2,3-dihydro-5,6,7-trimethylbenzo[b]furan (5.00 g, 78%) as a white solid, mp <50° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:13][CH2:14][C:15]([NH2:17])=[O:16].C(N(C(C)C)CC)(C)C>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([S:8]([NH:13][CH2:14][C:15]([NH2:17])=[O:16])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NCC(N)=O
Reactant: O=S(=O)(Cl)c1cccc(I)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CNS(=O)(=O)c1cccc(I)c1
Yield: 42.9 %

Procedure:
(3-Iodophenyl)sulphonyl chloride (0.303 g) was stirred with glycinamide hydrochloride (0.122 g) and diisopropylethylamine (0.3 ml) in DMF (4 ml) at 21° for 24 h. The mixture was evaporated to dryness and applied to a silica Bond Elut Cartridge (10 g). The cartridge was eluted with CH2Cl2, Et2O and EtOAc. This gave the title compound (0.146 g), LCMS RT=2.36 min, ES+ve 341 (MH)+
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1.[C:10]12[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:15]C(=O)O[C:11]2=[O:12]>C(O)C>[NH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=1[C:11]([NH:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[O:12]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCCn1cncn1
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCCn1cncn1
Temperature: 70 °C

Procedure:
A mixture of about 2.5 g of 1H-1,2,4-triazole-1-propanamine, about 3.26 g of isatoic anhydride and about 20 ml of ethanol was heated in an oil bath at about 70° C. for about 30 minutes and then concentrated. The residue was recrystallized from ethyl acetate and the desired product, mp 96°-98° C., was obtained.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]([CH2:12][CH2:13][O:14][CH3:15])[CH3:11])[N:3]=1.[Br:16][C:17]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:18]=1[CH:19]=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]([CH2:12][CH2:13][O:14][CH3:15])[CH3:11])[N:3]=2)=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: COCCN(C)c1nc(Cl)ccc1C#N
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCN(C)c1nc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Temperature: 80 °C
Yield: 74.1 %

Procedure:
To a solution of 6-chloro-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinonitrile (4) (11.6 g, 51.9 mmol) in DMF (anhydrous, 300 mL) were added 2-bromo-5-hydroxy-benzaldehyde (10.4 g, 51.9 mmol) and K2CO3 (14.3 g, 103.8 mmol). The reaction was heated at 80° C. for 16 hours. DMF was evaporated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 5%-30% EtOAc gradient, to afford 15 g (75% yield) of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.34 (s, 1H), 7.75-7.69 (m, 2H), 7.67 (d, J=8.6 Hz, 1 H), 7.28-7.23 (m, 1 H), 6.26 (d, J=8.6 Hz, 1 H), 3.56 (t, J=5.5 Hz, 2 H), 3.36 (t, J=5.5 Hz, 2 H), 3.25 (s, 3 H), 3.24 (s, 3 H).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([C:7]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]([C:16]3[CH:17]=[N:18][C:19]([N+:22]([O-])=O)=[CH:20][CH:21]=3)[N:8]=2)[O:4][C:3]1=[O:25]>C(#N)C>[NH2:22][C:19]1[N:18]=[CH:17][C:16]([N:9]2[C:10]([C:12]([F:14])([F:13])[F:15])=[CH:11][C:7]([C:5]3[O:4][C:3](=[O:25])[N:2]([CH3:1])[N:6]=3)=[N:8]2)=[CH:21][CH:20]=1
Reactant: Cn1nc(-c2cc(C(F)(F)F)n(-c3ccc([N+](=O)[O-])nc3)n2)oc1=O
Solvent: CC#N
Product: Cn1nc(-c2cc(C(F)(F)F)n(-c3ccc(N)nc3)n2)oc1=O

Procedure:
Step-6: 3-Methyl-5-(1-(6-nitropyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2(3H)-one: The title compound was prepared from step-5 intermediate by following the similar procedure sequentially as described in Step-5 and Step-6 of Intermediate-1. 1HNMR (400 MHz, CDCl3) δ 8.91(d, J=2.5 Hz, 1H), 8.48 (d, J=8.5 Hz, 1H), 8.31(dd, J=2.5 & 8.5 Hz, 1H), 7.37 (s, 1H), 3.53 (s, 3H); ESI-MS (m/z) 398 (M+acetonitrile).
Reaction SMILES: [CH3:1][C:2]1([CH2:14][CH:15]=[O:16])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.C[Si](C)(C)[C:19]([F:22])([F:21])[F:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:20][C:19]([F:22])([F:21])[CH:15]([OH:16])[CH2:14][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CSc1ccc2c(c1)C(C)(CC=O)CCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(C)(CC(O)C(F)(F)F)CCO2
Reaction time: 1 h
Yield: 104.9 %

Procedure:
To 383 mg (1.6 mmol) of (4-methyl-6-methylsulfanylchroman-4-yl)acetaldehyde and 0.335 mL (1.4 mmol) of trimethyl(trifluoromethyl)silane in 5 mL of tetrahydrofuran was added 3 drops of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. The mixture stirred for 1 hour and then an additional 1.8 mL (1.8 mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added. After 18 hours, the mixture was concentrated in vacuo and diluted with 1N aqueous HCl and extracted with three 50 mL portions of diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 0.45 g of 1,1,1-trifluoro-3-(4-methyl-6-methylsulfanylchroman-4-yl)propan-2-ol as a mixture of diastereomers. The crude oil was used without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[OH:17].[OH-].[K+]>O>[O:6]1[CH:3]([CH2:4][OH:5])[CH2:1][O:17][C:8]2[CH:9]=[CH:10][C:11]3[C:16]([C:7]1=2)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: Oc1ccc2ccccc2c1O
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: OCC1COc2ccc3ccccc3c2O1
Reaction time: 2.5 h
Yield: 74.1 %

Procedure:
Epichlorohydrin (2.32 g) was added dropwise to a stirred solution of 1,2-dihydroxynaphthalene (4.0 g) and potassium hydroxide (4.0 g) in water (32 ml) and the resulting mixture stirred at 60°-80° C. for 2.5 hours then poured into water (100 ml). The product was extracted into ether (6×100 ml), a small volume of methanol being added to aid solubility. The combined extracts were washed with aqueous sodium hydroxide solution (1M), then water, and dried over magnesium sulphate. The solvent was removed in vacuo to give crude 1-(naphtho[1,2-b]dioxan-2-yl)methanol (4.0 g) as a dark oil which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[Rh]>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.8 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenylpentanoic acid (Syn. Lett.; 1998; 637-639) (10.00 g, 34.2 mmol) in acetic acid (120 ml) was treated with 5% Rhodium on alumina catalyst, pressurised to 60 psi with hydrogen in a sealed vessel and stirred at room temperature for 17 hours. The mixture was filtered through a pad of Arbocel® and the solvent was removed from the filtrate under reduced pressure. The residue was azeotroped from toluene to afford the title compound (7.53 g).
Reaction SMILES: [CH2:1]([NH:17][CH2:18][CH2:19][NH2:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:21](OCC)(=[O:26])[CH2:22][C:23]([CH3:25])=O>>[CH2:1]([N:17]1[C:21](=[O:26])[CH2:22][C:23]([CH3:25])=[N:20][CH2:19][CH2:18]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNCCN
Reactant: CCOC(=O)CC(C)=O
Product: CCCCCCCCCCCCCCCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 284.1 g (1 mole) of N-hexadecylethylenediamine and 130.1 g (1 mole) of ethyl acetoacetate. At 160° to 170° C., 18 g of water and 46 g of ethanol were distilled off to obtain 4-hexadecyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:12]([N+:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[S:16][C:15]=1[CH3:23])[CH3:13].[Cl:24][C:25]([Cl:36])([Cl:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:24][C:25]([Cl:35])([Cl:36])[C:26]1[CH:34]=[CH:33][C:29]([C:30]([CH:23]=[C:15]2[N:14]([CH2:12][CH3:13])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16]2)=[O:31])=[CH:28][CH:27]=1
Reactant: CC[n+]1c(C)sc2ccccc21
Reactant: O=C(Cl)c1ccc(C(Cl)(Cl)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN1C(=CC(=O)c2ccc(C(Cl)(Cl)Cl)cc2)Sc2ccccc21

Procedure:
35 g (0.1 mol) of 3-ethyl-2-methyl-benzothiazolium p-toluenesulfonate are suspended in 300 ml of toluene, 28 g (0.11 mol) of p-trichloromethyl-benzoyl chloride are added, and 23 g (0.23 mol; 31.5 ml) of triethylamine are added dropwise at 15° C.
Reaction SMILES: N#N.[CH3:3][O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21].S(OC)(O[CH3:29])(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:3][O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][C:9](=[O:23])[N:10]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21])[CH3:29]
Reactant: COC(=O)CCCC(=O)Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COS(=O)(=O)OC
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCC(=O)N(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 22.5 h

Procedure:
To a 100 mL round bottom 3-neck flask equipped with stir bar, thermocouple, and N2 sweep were charged 16.67 g (53.6 mmol) of 4-(2,4-dinitro-phenylcarbamoyl)-butyric acid methyl ester and 50 mL (5 volumes vs. dinitroaniline) of acetonitrile at room temperature. To this clear yellow stirred solution was then added 6.09 mL (8.10 g, 64.2 mmol, 1.2 equiv) of dimethyl sulfate and 14.80 g (107 mmol, 2.0 equiv) of K2CO3. The mixture turned dark reddish orange with the addition and exhibited an exotherm of less than 5° C. The reaction was monitored periodically by HPLC Method A and was complete after 22.5 hours at room temperature.
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:13])[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[N:8][C:6]=2[N:7]=1.[O:14]([CH2:21][CH2:22][CH2:23][OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC([O-])(C)C.[K+]>CS(C)=O>[Cl:12][C:10]1[CH:9]=[N:8][C:6]2[N:7]=[C:2]([O:24][CH2:23][CH2:22][CH2:21][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:3][C:4](=[O:13])[C:5]=2[CH:11]=1
Reactant: OCCCOc1ccccc1
Reactant: O=c1[nH]c(Cl)nc2ncc(Cl)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]c(OCCCOc2ccccc2)nc2ncc(Cl)cc12
Yield: 2.5 %

Procedure:
A solution of 2,6-dichloro-3H-pyrido[2,3-d]pyrimidin-4-one (60 mg, crude), 3-phenoxy-1-propanol [6180-61-6] (127 mg, 0.84 mmol), and KOtBu (62 mg, 0.55 mmol) in DMSO (1 ml) was heated in a microwave oven to 180° C. for 15 min. After filtration, the title compound (2.3 mg, 6.9 Amok; 2.5%, MS: m/e=330.3 [M−H−]) was obtained from the reaction mixture by preparative, reverse-phase HPLC (Agilent Zorbax XdB C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 7 min, flow rate 30 ml/min).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][O:20]2)=[C:15]([CH3:22])[CH:14]=1)(=[O:12])=[O:11].[CH3:27][C:28]1([NH2:32])[CH2:31][O:30][CH2:29]1>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:20])[CH2:21][NH:32][C:28]2([CH3:27])[CH2:31][O:30][CH2:29]2)=[C:15]([CH3:22])[CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)c(C)c2)c(C)c1
Reactant: CC1(N)COC1
Solvent: CCO
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)CNC3(C)COC3)c(C)c2)c(C)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred solution of N-(2,4-dimethylphenyl)-N-isobutyl-3-methyl-4-(oxiran-2-yl)benzenesulfonamide (20 mg, 0.054 mmol) in ethanol at 25° C. was added 3-methyloxetan-3-amine (5.08 mg, 0.058 mmol). The reaction mixture was then stirred at 50° C. for 18 hours. Another portion of 3-methyloxetan-3-amine (5.08 mg, 0.058 mmol) was then added and the reaction stirred for a further 8 hours at 50° C. The reaction mixture was concentrated in vacuo and purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product, 9.3 mg. LCMS [LCMS2] Rt 1.25 min, m/z (ES+) 461 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3]1.N1C=CC=CC=1.[C:25](Cl)(=[O:27])[CH3:26]>ClCCl>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]1[C:25](=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CC1CCc2c(cccc2Oc2ccccc2)N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2cccc(Oc3ccccc3)c2CCC1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
A glass, screw-cap vial equipped with a magnetic stir bar was charged with a solution of rac-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (0.050 g, 0.21 mmol) in dichloromethane (1 mL) and pyridine (0.051 mL, 0.630 mmol). The solution was cooled to 0° C. and acetyl chloride (0.015 mL, 0.210 mmol) was added. The ice bath was removed and the reaction mixture stirred at rt. After 10 min, the reaction mixture was diluted with dichloromethane and washed with 1 N aqueous hydrochloric acid solution (2×1 mL) followed by 5% aqueous sodium chloride solution (1 mL). The organic layer was concentrated to a yellow oil, which crystallized upon standing. The crude product was purified by preparative thin layer chromatography (1×1000 micron plate, eluting with 2:1 hexanes-ethyl acetate) to yield 1-(2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.0189 g, 32%) as a nearly colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.13 (d, J=6.60 Hz, 3 H), 1.36-1.55 (m, 1H), 2.11-2.27 (m, 4H), 2.36 (br s, 1H), 2.85 (dt, J=16.04, 6.09 Hz, 1H), 4.88 (br s, 1H), 6.76 (d, J=8.80 Hz, 1H), 6.89-6.96 (m, 2H), 6.96-7.04 (m, 1H), 7.04-7.11 (m, 1H), 7.12-7.19 (m, 1H), 7.29-7.37 (m, 2H). MS (ESI, pos. ion) m/z 282 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH2:23][CH2:24][NH:25]4)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[H-].[Na+].[C:34](Cl)(=[O:36])[CH3:35].O>CN(C=O)C>[C:34]([N:25]1[C:26]2[C:22](=[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=4)[O:20][N:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:23][CH2:24]1)(=[O:36])[CH3:35]
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1C(F)(F)F)C(F)(F)F
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCc2c(-c3noc(-c4ccc(OC(C)C(F)(F)F)c(C(F)(F)F)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}indoline (100 mg) in DMF (1.0 ml) was added 60% NaH (10.9 mg) at 0° C., followed by stirring at room temperature for 0.5 hour. Acetyl chloride (24.1 μl) was added thereto at 0° C., followed by stirring at room temperature for 3 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, n-hexane:EtOAc=90:10 to 60:40) to obtain 1-acetyl-4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}indoline (56.8 mg) as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Br:20]Br>C(O)C>[Br:20][C:15]1[CH:14]=[N:13][C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=3)[N:9]=[CH:10][C:11]=2[C:16]=1[OH:17]
Reactant: COc1ccc(Cn2ncc3c(O)ccnc32)cc1
Reactant: BrBr
Solvent: CCO
Product: COc1ccc(Cn2ncc3c(O)c(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
A solution of 1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (10.00 g, 39.17 mmol, prepared as described in WO 2007/103308) in absolute ethanol (220 mL) was cooled to 0° C., treated dropwise with bromine (2.15 mL, 43.09 mmol) and stirred at 0° C. for 30 minutes. The ice bath was then removed, and the mixture was allowed to warm to room temperature. After 30 minutes, water (150 mL) and concentrated HCl (10 mL) were added to the slurry, and the mixture was stirred at room temperature for 10 minutes. The solid formed was filtered and washed with water (3×20 mL) followed by EtOH (2×20 mL). The solid collected was triturated with CH3CN, filtered, washed with additional CH3CN (2×10 mL), and air dried to provide 5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (10.90 g, 83% yield) as a solid. LCMS (APCI+) m/z 333.9 (M+H)+, Retention time=2.33 minutes.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>>[C:18]1([CH3:22])[CH:19]=[CH:20][CH:21]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:17]=1
Reactant: Cc1cccc(I)c1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccc(C)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (90 mg, 0.48 mmol) and iodo-3-methylbenzene (0.07 mL, 0.55 mmol) according to the general procedure IB to give 42 mg (36%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:30→1:10). Rf: 0.29 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.46-7.43 (m, 2H), 7.35-7.31 (m, 2H), 7.22-7.12 (m, 4H), 3.67 (s, 3H), 2.99-2.93 (t, 2H, J=7.8 Hz), 2.66-2.61 (t, 2H, J=7.8 Hz), 2.35 (s, 3H); 13CNMR (CDCl3) δ 173.1, 140.8, 138.0, 132.1, 131.7, 129.1, 128.6, 128.3, 128.2, 123.1, 121.3, 89.3, 88.9, 51.6, 35.4, 30.8, 21.2; ESI-MS m/z 301.1 (MNa+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH2:9][C:10]2=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1CCc2ccc(Br)cc21

Procedure:
3-(4-Bromophenyl)propionic acid (162 g, 706 mmol) and thionyl chloride (155 mL, 2120 mmol) were refluxed for 90 minutes. The thionyl chloride was then removed under vacuum to yield an amber oil. This oil, aluminum chloride (109 g, 816 mmol), and dichloromethane (1000 mL) were refluxed for 90 minutes and then poured onto ice. Dilute hydrochloric acid was added and the mixture was extracted with diethyl ether. The organic layer was washed with 2N hydrochloric acid, water, aqueous sodium bicarbonate, water, and brine. The product was flash chromatographed on a 25×7 cm silica gel column and eluted with ethyl acetate/dichloromethane (5:95) to obtain a pale brown solid after removing solvent under vacuum, (142 g, 95%), 107-109° C. m.p.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[C:8]1([CH3:20])[CH:13]=[CH:12][C:11]([S:14]([N:17]=[C:18]=[O:19])(=[O:16])=[O:15])=[CH:10][CH:9]=1>C1C=CC=CC=1>[C:8]1([CH3:20])[CH:9]=[CH:10][C:11]([S:14]([NH:17][C:18]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[O:19])(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CC(=O)CC(C)=O
Solvent: c1ccccc1
Product: CC(=O)C(C(C)=O)C(=O)NS(=O)(=O)c1ccc(C)cc1

Procedure:
Reaction of equimolar amounts of 2,4-pentanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 3-(N-p- TOLUENESULFONYLCARBAMOYL)-2,4-PENTANEDIONE, m.p. 137°-139.5° C. (corr.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH:15](=O)[CH3:16]>>[CH2:15]([NH:14][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1)[CH3:16]
Reactant: Nc1ccc(-c2ccc(F)cc2)cn1
Reactant: CC=O
Product: CCNc1ccc(-c2ccc(F)cc2)cn1

Procedure:
Compound 70A was reacted with acetaldehyde in a manner analogous to Compound 63C to give the title product. 400 MHz 1H NMR (DMSO-d6) δ ppm 1.1 (t, 3H) 3.2 (q, 2H) 6.6 (m, 2H) 7.2 (m, 2H) 7.5 (m, 3H) 8.2 (d, J=2.0 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1OC
Reactant: c1c[nH]cn1
Product: COc1ccc(CNc2nc(-n3ccnc3)nc3sc(C)c(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-5,6-dimethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.