Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:28]3[C:29]([CH:32]=[O:33])=[CH:30][CH:31]=[C:27]3[C:8]3([CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH3:25])[CH:16]=4)[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:34]=1.[Mn]([O-])(=O)(=O)=[O:36].[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:28]3[C:29]([C:32]([OH:36])=[O:33])=[CH:30][CH:31]=[C:27]3[C:8]3([CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH3:25])[CH:16]=4)[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:34]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2c(C=O)ccc23)ccc1OC(C)C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2c(C(=O)O)ccc23)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
To a solution of 7-chloro-1′-(4-isopropoxy-3-methylbenzoyl)spiro-[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (130 mg, 0.27 mmol) in acetone (1.5 mL) was added a solution of potassium permanganate (43 mg, 16 μL, 0.27 mmol) in water (1.5 mL) and acetone (1.5 mL) dropwise at 0° C. The mixture was allowed to stir at room temperature for 2 h before it was concentrated onto Celite from methanol. Column chromatography on the residue (0-20% EtOAc/CH2Cl2) gave 7-chloro-1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]-pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carboxylic acid (13%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([C:31]4[N:35](COCC[Si](C)(C)C)[C:34]5[CH:44]=[CH:45][CH:46]=[CH:47][C:33]=5[N:32]=4)[C:19](=[O:30])[N:20](COCC[Si](C)(C)C)[N:21]=3)[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[NH:35]1[C:34]2[CH:44]=[CH:45][CH:46]=[CH:47][C:33]=2[N:32]=[C:31]1[C:18]1[C:19](=[O:30])[NH:20][N:21]=[C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:15]=2)[CH:17]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccnc(NCCN3CCOCC3)n2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]nc(-c2ccnc(NCCN3CCOCC3)n2)cc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
88 mg of 6-[2-(2-morpholin-4-ylethylamino)pyrimidin-4-yl]-2-(2-trimethylsilanyl-ethoxymethyl)-4-[1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-2H-pyridazin-3-one are dissolved in 2 ml of a 1:1 mixture of dichloromethane and trifluoroacetic acid, and the mixture is stirred at room temperature for 2 hours. The volatile components are then distilled off, the residue is dissolved in 1 ml of methanol, and 1 ml of a two molar aqueous sodium hydroxide solution is added. The solution is stirred at room temperature for 12 hours and then put directly onto the preparative RP-HPLC (0-100% acetonitrile (+0.05% formic acid) in water (+0.05% formic acid)) to isolate the product.
Reaction SMILES: CN1CCOCC1.[N:8]1([C:14]2[N:19]=[CH:18][C:17]([C:20]3([C:23]([N:25]4[CH2:29][CH2:28][C@@:27]5([C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=6[C:31](=[O:38])[O:30]5)[CH2:26]4)=[O:24])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH:39]1([C:42](O)=[O:43])[CH2:41][CH2:40]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(#N)C>>[CH:39]1([C:42]([N:11]2[CH2:12][CH2:13][N:8]([C:14]3[N:19]=[CH:18][C:17]([C:20]4([C:23]([N:25]5[CH2:29][CH2:28][C@@:27]6([C:33]7[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=7[C:31](=[O:38])[O:30]6)[CH2:26]5)=[O:24])[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[CH2:9][CH2:10]2)=[O:43])[CH2:41][CH2:40]1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCNCC5)nc4)CC3)C2)c2ccccc21
Reactant: O=C(O)C1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN1CCOCC1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCN(C(=O)C6CC6)CC5)nc4)CC3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methylmorpholine (2.0×10−1 μL, 0.00018 mol) was added to a mixture of (1R)-1′-{[1-(6-piperazin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (15 mg, 0.000036 mol, this compound was prepared in a way similar to that described in example 163), cyclopropanecarboxylic acid (3.4 μL, 0.000043 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (19 mg, 0.000043 mol) in acetonitrile (0.7 mL, 0.01 mol). The reaction mixture was stirred at room temperature overnight. The crude product was purified by prep-LCMS. LC/MS: 487.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C1C=CN=CC=1)C>[C:16]([NH:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(OC)c2c(N)ccnc12
Agent: CN(C)c1ccncc1
Product: COc1ccc(OC)c2c(NC(C)=O)ccnc12

Procedure:
A suspension of 3 g (14.7 mmol) of 4-amino-5,8-dimethoxyquinoline and of 0.72 g (5.88 mmol) of DMAP in 30 mL of acetic anhydride is stirred at ambient temperature for 24 hours. After concentrating on a rotary evaporator, the reaction medium is washed with 40 mL of saturated NaHCO3 solution and then extracted with CHCl3 (3 times 50 mL). The extracts are dried over MgSO4 and the solvent is evaporated off, followed by evaporation of the remaining acetic anhydride by azeotropic entrainment with benzene. 2.7 g of the expected derivative are obtained in the form of a yellow powder.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21].ClCCl>CCCCCC.C(OCC)(=O)C>[CH2:1]([NH:7][C:20]([C:16]1[O:15][CH:19]=[CH:18][CH:17]=1)=[O:21])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccco1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(NCc1ccco1)c1ccco1

Procedure:
N-furfuryl-2-furamide was prepared by adding dropwise to a mixture of furfurylamine (7.44 g; 7 mmol; ex Aldrich) and triethylamine (35.6 g; 352 mmol) in dichloromethane 2-furoyl chloride (23 g; 176 mmol) at a temperature of 0 to 5° C. The product obtained was washed with water, dried with magnesium sulphate and evaporated. Subsequently, the product so obtained was purified by flash chromatography (silica, hexane/ethyl acetate as eluant) and 14 g (97% yield) of the product was recovered.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][OH:14])[O:9][C:8](=[O:15])[C:7]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:6]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.[O-2].[O-2].[Mn+4]>[O:15]=[C:8]1[C:7]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:6]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:5]2[C:10](=[CH:11][C:12]3[C:13](=[O:14])[O:1][CH2:2][C:3]=3[CH:4]=2)[O:9]1
Reactant: CCOC(=O)Cc1c(-c2ccccc2)c2cc(CO)c(CO)cc2oc1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)Cc1c(-c2ccccc2)c2cc3c(cc2oc1=O)C(=O)OC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
A solution of ethyl 2-[6,7-bis(hydroxymethyl)-2-oxo-4-phenyl-2H-chromen-3-yl]acetate (150 mg) in dichloromethane (3 ml) was combined with manganese dioxide (1.5 g), and stirred at room temperature overnight. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to obtain the residue, which was recrystallized from THF to obtain the title compound (98 mg, yield: 66%).
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:14]3[C:10](=[CH:11][N:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[N:13]=3)[CH:9]=2)=[CH:5][CH:4]=1.N[C@H](C(O)=O)CCSC.[OH-].[Na+].C(=O)(O)[O-].[Na+]>CS(O)(=O)=O.O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:12]2[CH:11]=[C:10]3[C:14]([CH:15]=[CH:16][C:8]([O:7][C:6]4[CH:23]=[CH:24][C:3]([OH:2])=[CH:4][CH:5]=4)=[CH:9]3)=[N:13]2)[CH:18]=1
Reactant: COc1ccc(Oc2ccc3nn(-c4cccnc4)cc3c2)cc1
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: O=C([O-])O
Solvent: O
Product: Oc1ccc(Oc2ccc3nn(-c4cccnc4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 104.6 %

Procedure:
A solution of 5-(4-methoxy-phenoxy)-2-pyridin-3-yl-2H-indazole (0.050 grams, mmol) in 1 mL of methanesulfonic acid was treated with 0.1 grams of methionine. After stirring for 24 hours at room temperature, the mixture was treated with 0.6 grams of sodium hydroxide in 25 mL of water with cooling in an ice bath, neutralized with aqueous sodium bicarbonate, extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo, affording 0.05 grams of 4-(2-Pyridin-3-yl-2H-indazol-5-yloxy)-phenol as a colorless syrup. MS: 304.4 [M+H]+
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].C(N(C(C)C)CC)(C)C.[I:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[I:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][C:3]2([O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]2[NH2:5])[OH:2])=[CH:26][CH:25]=1
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: BrCc1ccc(I)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1(O)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.4 %

Procedure:
Thus, a slurry of glucosamine hydrochloride (0.7 g) and diisopropylethylamine (0.6 mL) in DMF (2.0 mL) was stirred at 80° C. for 30 minutes. A solution of 4-iodobenzylbromide (0.4 g) in DMF (2 mL) was added to the reaction mixture, and the resulting mixture stirred for 18 hours. After the reaction mixture was cooled to room temperature, the precipitated solid was removed from the supernatant by decanting. Volatiles were removed from the supernatant, and the resulting residue was separated on a si-gel column using 10% aqueous MeCN as the eluent to yield 50 mg of pure 4-iodobenzyl glucosamine (compound TP012 in the scheme above). The purity of 4-iodobenzyl bromide, which can vary greatly from batch to batch if obtained from commercial suppliers, will affect the yields of this reaction accordingly. The compound 4-Iodobenzyl galactosamine can be prepared using a similar reaction scheme, starting from galactosamine hydrochloride and iodobenzyl bromide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH:15]([C:17](=[O:20])[CH2:18][CH3:19])[CH3:16].Cl>CN(C=O)C>[OH:9][B:8]1[C:4]2[CH:3]=[C:2]([O:1][CH:15]([C:17](=[O:20])[CH2:18][CH3:19])[CH3:16])[CH:11]=[CH:10][C:5]=2[CH2:6][O:7]1
Reactant: OB1OCc2ccc(O)cc21
Reactant: CCC(=O)C(C)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)C(C)Oc1ccc2c(c1)B(O)OC2
Temperature: 0 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
H181 (150 mg, 1.0 mmol) was dissolved in DMF (6.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 160 mg, 4.0 mmol) and 2-bromopentan-3-one (660.12 mg, 4.0 mmol). The reaction mixture was stirred for 1 d then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (88.9 mg, 38% yield). 1H NMR (400 MHz, CDCl3): δ 7.21 (d, J=8.1 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 6.98 (dd, J=8.4 & 2.7 Hz, 1H), 5.00 (s, 2H), 4.67 (q, J=6.8 Hz, 1H), 2.73-2.61 (m, 1H), 2.49-2.39 (m, 1H), 1.47 (d, J=6.8 Hz, 3H) and 0.99 (t, J=7.2 Hz, 3H) ppm; Mp: 72-74° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[N:20]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:3]([F:28])[CH:4]=2)(=[O:10])=[O:9])=[C:13]([N:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[N:20]2)[CH:14]=1
Reactant: O=S(=O)(Nc1ccc(Cl)cc1-n1nnc2ncccc21)c1ccc(Br)c(F)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1ccc(Cl)cc1-n1nnc2ncccc21)c1ccc(N2CCOCC2)c(F)c1
Yield: 44.2 %

Procedure:
4-Bromo-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-3-fluoro-benzensulfonamide (synthesized according to general procedure G, 180 mg, 0.37 mmol) was dissolved in 3 ml of anhydrous dimethylformamide under an atmosphere of nitrogen. To this mixture was added morpholine (161 mg, 1.85 mmol), 2,2′-bis(diphenylphosphine)-1,1′-binaphthyl (BINAP) (34 mg, 0.055 mmol), potassium phosphate tribasic monohydrate (511 mg, 2.22 mmol), and tris(dibenzylideneacetone) dipalladium(0) (Pd2(dba)3) and the resultant mixture was heated at 80° C. overnight. The following day, the reaction mixture was partitioned with a saturated solution of sodium bicarbonate and dichloromethane and the aqueous layer was extracted three times with dichloromethane. The combined organics were subsequently dried over magnesium sulfate, concentrated in vacuo, and purified by reverse phase HPLC, followed by silica gel chromatography employing ethyl acetate:hexanes (1:1), to afford 80 mg of the desired product as a white powder: MS (ES) M+H expected 489.1, found 489.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([O:19][CH3:20])[CH:3]=1.[Cl-].[Li+].CS(C)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc(Br)cc1OC
Temperature: 120 °C
Reaction time: 20 h
Yield: 42.4 %

Procedure:
A mixture of diethyl 2-(4-bromo-2-methoxyphenyl)malonate (1213 mg, 3.500 mmol), lithium chloride (620 mg, 14.6 mmol), and DMSO (6 ml) was stirred at 120° C. for 20 hours, then at 150° C. for 4 hours, and again at 120° C. for 20 hours. The reaction was cooled to room temperature, diluted with 25 mL of water, and extracted with ethyl acetate-heptane mixture (1:1). The extract was washed with brine (2 times), dried over magnesium sulfate, and loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 0% to 30% of ethyl acetate in heptane gave the title compound (405 mg, 42% yield over two steps). GCMS (ES+) 272 (M+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: O=C1COc2ccc(O)cc2N1
Product: COc1cc2c(Oc3ccc4c(c3)NC(=O)CO4)ncnc2cc1OCC1CCN(C)CC1
Yield: 0.1 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mol), (prepared as described for the starting material in Example 10), was reacted with 6-hydroxy-2H-4H-1,4-benzoxazin-3-one (83 mg, 0.5 mol), (J. Chem. Soc. C, 1971, 2696), to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(3-oxo-2H-4H-1,4-benzoxazin-6-yloxy)quinazoline (158 mg, 88%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].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>[F:9][C:4]1[CH:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: Ic1ccccc1
Reactant: Cc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Thirty milliliters of a 1.6-M-n-butyllithium hexane solution and a solution of 9.21 g of 4-bromo-2-fluorotoluene in 30 ml of tetrahydrofuran were added in this order to 30 ml of tetrahydrofuran which had been cooled to −78° C. in a nitrogen atmosphere, and the mixture was then stirred at −78° C. for 1 hour. A solution containing 6.64 g of zinc chloride which had been dehydrated through heat-melting under reduced pressure in 30 ml of tetrahydrofuran was added thereto at −78° C., and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to a solution of 6.63 g of iodobenzene and 0.52 g of tetrakis(triphenylphosphine)palladium (0) in 30 ml of tetrahydrofuran at room temperature, and the mixed solution was stirred for 24 hours. The reaction solution was diluted with 300 ml of ethyl acetate, and the dilute solution was extracted with the addition of 10% hydrochloric acid. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried, and then concentrated. The residue was purified through silica-gel column chromatography (eluent: hexane) to give 6.00 g of oily 3-fluoro-4-methylbiphenyl.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl.C(N(CC)CC)C.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1.[Cu]>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Clc1nc2ccccc2s1
Reactant: CCOC(=O)[C@@H]1CCCCN1
Agent: [Cu]
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCCCN1c1nc2ccccc2s1
Yield: 81.9 %

Procedure:
2-Chloro-1,3-benzothiazole (503 mg) was added to a suspension of ethyl (2S)-2-piperidinecarboxylate (471 mg) [J.A.C.S. (1993), 115(22), 9925-9938], triethylamine hydrochloride (414 mg) and copper powder (38 mg) in xylene (5 ml). The reaction mixture was refluxed for 28 hours, after which time ethyl acetate (20 ml) was added to the cooled mixture and the solids filtered off. The organic layer was washed with water, dried over magnesium sulphate and the solvent removed under reduced pressure to afford ethyl (2S)-1-(1,3-benzothiazol-2-yl)-2-piperidinecarboxylate (705 mg) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:14])=O.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.Cl.[NH2:45][CH:46]1[CH:53]2[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:55][CH:47]1[CH2:48]3)[CH2:52]2>ClCCl.CN(C=O)C.O>[CH:47]12[CH2:55][CH:51]3[CH2:50][CH:49]([CH2:54][CH:53]([CH2:52]3)[CH:46]1[NH:45][C:12]([C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1])=[O:14])[CH2:48]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: Cn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reaction time: 1 h
Yield: 38 %

Procedure:
5-Chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid (91 mg, 0.4 mmol, CAS#: 128455-63-0, purchased from Maybridge) was dissolved in a mixture of dry dichloromethane (3.2 mL) and dry DMF (0.8 mL). DIPEA (0.28 mL, 1.6 mmol) and TSTU (145 mg, 0.44 mmol) were added to the above mixture. After the mixture was stirred for 1 h, the appearance of active ester was detected by LC-MS. Then 2-aminoadamantane hydrochloride (75 mg, 0.4 mmol) was added. After another 2 hours water was added and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane. The combined organic phases were dried under vacuum and purified by C-18 reversed phase HPLC with a gradient of 10-100% acetonitrile/water to give 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (55 mg, 38%). Mass spectrum: m/z: 362.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]1[O:13][CH3:14].[Cl:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH2:27][C@H:28]([NH2:30])[CH3:29].C(N(CC)CC)C>C(O)C>[Cl:21][C:22]1[CH:26]=[CH:25][S:24][C:23]=1[CH2:27][C@H:28]([NH:30][C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:11]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]1[O:13][CH3:14])[CH3:29]
Reactant: C[C@@H](N)Cc1sccc1Cl
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)ncnc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N[C@H](C)Cc3sccc3Cl)ncnc21

Procedure:
A solution of 6-chloro-9-(2′-O-methyl-b-D-ribofuranosyl)-9H-purine (prepared as in EP Publication No. 0378518) (0.28 g), 2-(3-chloro-2-thienyl)-(1R)-1-methylethylamine (0.163 g), and triethylamine (0.5 mL) in ethanol (30 mL) is refluxed for about 18 hours, cooled and concentrated in vacuo. The residue is purified by flash chromatography, eluting with 10% methanol in methylene chloride, followed by crystallization from hexane/ethyl acetate, to give the desired product, m.p. 75-76° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C1CCC(N=C=NC2CCCCC2)CC1.[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[O:40][C:39]([CH2:41][CH2:42][NH2:43])=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35].C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[O:40][C:39]([CH2:41][CH2:42][NH:43][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[O:12])=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
Indazole-3-carboxylic acid (30 mg; 0.182 mmol), DCC (56 mg, 0.273 mmol) and DMAP (2 mg) were dissolved in DCM:DMF (1:1, 4 ml). 2-(5-(3,4-dichlorophenyl)furan-2-yl)ethanamine (46 mg, 0.182 mmol) was added and the reaction mixture was stirred for overnight at RT. DCM (30 ml) was added and organic layer washed with water (3×15 ml). Combined organic phases were dried over Na2SO4, evaporated and purified by chromatography (silica column, eluent: 1% MeOH/DCM) to give 25 mg (34%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.00 (t, 2H), 3.63 (q, 2H), 6.37 (d, 1H), 7.02 (d, 1H), 7.23 (t, 1H), 7.41 (t, 1H), 7.60 (d, 1H), 7.61 (d, 2H), 7.85 (d, 1H), 8.16 (d, 1H), 8.54 (d, 1H), 13.56 (s, 1H).