Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]2)[CH2:31]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:31][CH:32]([N:34]5[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]5)[CH2:33]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C1CN(C2CNC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCNC(=O)C4)C3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), 4-azetidin-3-ylpiperazin-2-one (44 mg, 0.28 mmol) and 4 Å powdered molecular sieves (250 mg) in MeOH (2 mL) and DCE (5 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (108 mg, 0.51 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-7%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 514 as a yellow foam (42 mg, 31%). LCMS (Method I): RT 2.28 min [M+H]+ 531.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.79-7.74 (m, 1 H); 7.31-7.24 (m, 2 H); 5.93 (bs, 1 H); 4.35 (m, 4 H); 3.94 (s, 2 H); 3.94-3.80 (m, 7 H); 3.66 (bs, 2 H); 3.43-3.33 (m, 4 H); 3.21 (s, 3 H); 3.06 (s, 2 H); 2.58 (t, J=5.37 Hz, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[OH:10].[CH:11]([CH:13]=O)=O>CO>[Br:9][C:5]1[CH:4]=[C:3]([OH:10])[C:2]2[N:1]=[CH:11][CH:13]=[N:8][C:7]=2[CH:6]=1
Reactant: Nc1cc(Br)cc(O)c1N
Reactant: O=CC=O
Solvent: CO
Product: Oc1cc(Br)cc2nccnc12
Reaction time: 8 h

Procedure:
As shown in step 6-v of Scheme 6, 2,3-diamino-5-bromophenol (6.0 g, 29.5 mmol) was dissolved in methanol and to this solution was added glyoxal (3.77 g, 2.98 mL, 64.9 mmol) and stirred overnight. The reaction mixture was concentrated under reduced pressure to a minimum volume and the resulting tan solid collected by filtration and dried under high vacuum to produce 7-bromoquinoxalin-5-ol (compound 1017), which was used as is in subsequent reactions without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29](OCC)=[O:30])=[CH:23][CH:22]=1.FC1C=CC(C=CC(O)=O)=CC=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[C:29](=[O:30])[CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:13][CH:14]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncn2)cc1
Reactant: CCOC(=O)CCc1ccc(F)cc1
Agent: O=C(O)C=Cc1ccc(F)cc1
Agent: [Li]CCCC
Product: N#Cc1ccc(C(C(=O)CCc2ccc(F)cc2)n2cncn2)cc1

Procedure:
1-[1-(4-cyanophenyl)-4-(4-fluorophenyl)-2-oxobutyl]-1,2,4-triazole is prepared according to the procedure described in Example 1 starting from 1-(4-cyanobenzyl)-1,2,4-triazole (1.7 g, 0.0092 mol), n-BuLi (0.0108 mol) and ethyl 3-(4-fluorophenyl)propionate (2.3 g, 0.0117 mol) prepared from 4-fluorocinnamic acid by esterification and hydrogenation. The product is purified by flash chromatography methylene chloride-methanol (95:5) as eluent.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8](C(O)=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>[Cu].Cl>[Cl:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2c(Cl)cccc2s1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: Clc1cccc2sccc12
Temperature: 25 °C

Procedure:
A mixture of 4-chlorobenzo[b]thiophene-2-carboxylic acid (2 g prepared in a manner similar to that described in J. Chem. Res. (S), 1978, 10), copper powder (0.82 g) and quinoline (20 ml) was stirred under nitrogen at 180° C. for 2 hours then cooled to ambient temperature and acidified by the addition of 2M hydrochloric acid (50 ml). The product was extracted into ether (50 ml), the extract was dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 5:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 4-chlorobenzo[b]thiophene (1.49 g) as a pale yellow oil which was used without further purification.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][CH:21]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH2:36])[CH:24]([CH3:26])[CH3:25])[CH3:22]>C(#N)C>[CH3:26][CH:24]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH:36][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH:21]([CH3:20])[CH3:22])[CH3:25]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CC(C)N(CC1CCCCN1CCN)C(C)C
Solvent: CC#N
Product: CC(C)N(CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21)C(C)C
Yield: 34 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[[bis(methylethyl)amino]methyl]-piperidin-l-yl]ethanamine in a yield of 34% of theory. Colourless crystals, m.p. 181°-182° C. (acetonitrile using activated charcoal).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:34])=[N:13][C:14]2[N:15]([N:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:27]=2)[C:16]=1[N:17]1[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([O:5][CH:6]([C:11]1[C:12]([CH3:34])=[N:13][C:14]2[N:15]([N:25]=[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:27]=2)[C:16]=1[N:17]1[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH2:22]1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2nc(-c3ccccc3)nn2c1N1CCC(C)(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc2nc(-c3ccccc3)nn2c(N2CCC(C)(C)CC2)c1C(OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To a solution of methyl 2-tert-butoxy-2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)acetate (25 mg, 0.054 mmol) in dioxane (0.8 ml) was added sodium hydroxide (0.8 mL, 0.8 mmol). The resulting mixture was warmed to 50° C. and stirred for 4 h. then filtered and purified by Pre-HPLC to afford 2-tert-butoxy-2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)acetic acid (18 mg, 0.039 mmol, 72.8% yield). 1H-NMR (400 MHz, CDCl3) δ 1.17 (6 H, s), 1.30 (9 H, s), 1.57-1.61 (2 H, m), 1.70-1.72 (2 H, m), 2.70 (3H, s), 5.83 (1 H, s), 7.49-7.54 (3 H, m), 8.35-8.37 (2 H, m).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[C:15](=[O:16])[N:14]3[C:17]4([NH:23][C:24](=[O:25])[C:13]3=[C:12]([CH3:26])[CH:11]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:4]=1[O:27][CH3:28].[CH:29]([N:32](CC)C(C)C)(C)[CH3:30].BrCC#N>CN(C)C=O.[Cl-].[NH4+]>[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[C:15](=[O:16])[N:14]3[C:17]4([NH:23][C:24](=[O:25])[C:13]3=[C:12]([CH3:26])[CH:11]=2)[CH2:22][CH2:21][N:20]([CH2:30][C:29]#[N:32])[CH2:19][CH2:18]4)[C:4]=1[O:27][CH3:28]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1c(N)ncnc1Nc1cc(C)c2n(c1=O)C1(CCNCC1)NC2=O
Agent: Cl
Agent: N#CCBr
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1c(N)ncnc1Nc1cc(C)c2n(c1=O)C1(CCN(CC#N)CC1)NC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-((6-Amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione hydrochloride (5, 0.18 g, 0.44 mmol) was dissolved in dimethylformamide (5 mL). To this mixture N,N-diisopropylethylamine (0.23 g, 1.76 mmol) was added followed by bromoacetonitrile (79 mg, 0.66 mmol). The reaction mixture was stirred at room temperature for 2 h. After completion the reaction mixture was diluted with saturated ammonium chloride solution (50 mL). Yellow precipitate was filtered and dried under reduced pressure. The compound was then purified by prep purification to afford 2-(6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile (Cpd. No. 243) as white solid. Yield: 40 mg, 22%; MS (ESI) m/z 411.20 [M+1]+; 1H NMR (400 MHz, DMSO-d6 with d1-TFA) δ 8.37 (s, 1H), 8.27 (s, 1H), 4.49 (s, 2H), 3.76 (s, 3H), 3.74-3.71 (m, 2H), 3.56-3.40 (m, 4H), 2.43 (s, 3H), 1.90-1.87 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[C:6]([CH3:20])([CH3:19])[CH2:5]2.[CH3:21][O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:21][O:22][C:23](=[O:28])[C:24]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:7]2[C:6]([CH3:20])([CH3:19])[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[NH:8]2)[CH:13]=1)([CH3:26])[CH3:25]
Reactant: CC1(C)Cc2cc(Cl)ccc2NC1c1cccc(N)c1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(Cl)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 22.2 %

Procedure:
A mixture of 3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (1.5 g, 5.25 mmol), 2-bromo-2-methyl-propionic acid methyl ester (2.85 g, 15.7 mmol) and potassium carbonate (3.62 g, 26.25 mmol) in N,N-dimethylformamide (10 mL) was stirred at 25° C. for 5 d. Then the reaction mixture was extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (30% ethyl acetate/hexanes) to afford 2-[3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid methyl ester (450 mg, 22%) as a brown oil: LC/MS m/e calcd for C22H27ClN2O2 (M+H)+: 387.93, observed: 387.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:23])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=2)[C:10](=O)[CH2:9]1.[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:23])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]=2)[C:10](=[N:29][NH:28][C:25]([NH2:27])=[NH:26])[CH2:9]1
Reactant: Cc1c2c(nn1-c1ccccc1)CC(c1ccccc1Cl)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1c2c(nn1-c1ccccc1)CC(c1ccccc1Cl)CC2=NNC(=N)N
Yield: 190.9 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-2-phenyl-4,5,6,7-tetrahydroindazol-4-one (0.6 g), aminoguanidine hydrochloride (0.24 g), concentrated hydrochloric acid (0.45 ml), water (0.45 ml) and ethanol (20 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol-water to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-2-phenyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 150) (0.73 g) as colorless crystals.
Reaction SMILES: C([S@]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([CH2:21][OH:22])[CH:11]=1)[CH3:9])=O)(C)(C)C.[ClH:23].CO>CO>[ClH:23].[NH2:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([CH2:21][OH:22])[CH:11]=1)[CH3:9]
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(NS(C)(=O)=O)c(CO)c1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)c1ccc(NS(C)(=O)=O)c(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of N-[4-((1R)-1-{[(R)-tert-butylsulfinyl]amino}ethyl)-2-(hydroxymethyl)phenyl]methanesulfonamide (3.6 g,10 mmol) in methanol (30 ml) was added hydrogenchloride-methanol solution (30 ml). The solution was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The given residue was recrystallized from methanol-diethyl ether. The precipitate was then filtered, washed with diethyl ether and collected to furnish 2.5 g (87% yield) of the title compound as a yellow oil.
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[CH:3]=1.C([Mg]Cl)(C)C.CON(C)[C:29]([C:31]1[CH:35]=[C:34]([CH3:36])[O:33][N:32]=1)=[O:30]>C1COCC1>[CH3:36][C:34]1[O:33][N:32]=[C:31]([C:29]([C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)[CH:3]=2)=[O:30])[CH:35]=1
Reactant: Cc1cccc(Cn2cc(I)c(=O)c3ccccc32)n1
Reactant: CON(C)C(=O)c1cc(C)on1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cccc(Cn2cc(C(=O)c3cc(C)on3)c(=O)c3ccccc32)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To the solution of 3-Iodo-1-(6-methyl-pyridin-2-ylmethyl)-1H-quinolin-4-one (300 mg, 0.82 mmol, 1.2 eq) in THF (2 ml), was added isopropylmagnesium chloride in THF (0.88 mL, 1.76 mmol, 2.1 eq) slowly at −40° C. The reaction mixture was warmed to room temperature and stirred for 60 min, followed by the addition of 5-Methyl-isoxazole-3-carboxylic acid methoxy-methyl-amide (116 mg, 0.0.68 mmol, 1 eq). The mixture was stirred overnight, quenched with water and purified with HPLC to give the desired product (25 mg). LCMS observed for (M+H)+: 360.1.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.S(Cl)([Cl:23])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:23][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1
Reactant: CN1C(=O)CCc2nc(-c3cncc(CO)c3)ccc21
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)CCc2nc(-c3cncc(CCl)c3)ccc21
Temperature: 3.5 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
At 0° C., 6-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one (170 mg, 0.63 mmol) in DCM (15 mL) was treated with thionyl chloride (0.32 mL, 4.0 mmol). After the addition, the reaction mixture was allowed to stir at 2-5° C. for 2 hours before it was poured into satd. aq. NaHCO3 solution (50 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give 6-(5-chloromethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one (156 mg, 86.3%) as yellow oil. MS: 288.1 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][OH:34])[N:18]=[C:17]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:42].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:16]=[C:17]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[N:18]=[C:19]([O:30][CH2:31][CH2:32][C:33]([OH:42])=[O:34])[C:20]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCCO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Yield: 15.6 %

Procedure:
4-t-Butyl-N-[6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyl]-benzenesulfonamide (800 mg) was dissolved in dimethylformamide (40 ml). Pyridinium dichromate (2.63 g) was added to the solution, and the resultant mixture was stirred for 14 hours at room temperature. Ethyl acetate was added to the reaction mixture, followed by successive washing with 0.5N-HCl, water, and brine. The organic layer was dried over anhydrous sodium sulfate and, evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=25:1), to thereby obtain 128 mg (yield: 16%) of the title compound as a white powder.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[C:12]3/[C:13](=[O:21])[NH:14][C:15]4[C:20]/3=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:8][CH:9]=2)[NH:4][N:3]=1.I[C:23]1C2C(=CC(C=O)=CC=2)NN=1.CN1C2C(=CC=CC=2)CC1=O>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[C:12]3/[C:13](=[O:21])[N:14]([CH3:23])[C:15]4[C:20]/3=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2c(I)n[nH]c2c1
Agent: CN1C(=O)Cc2ccccc21
Product: CN1C(=O)/C(=C/c2ccc3c(I)n[nH]c3c2)c2ccccc21

Procedure:
According to the method described for (E)-3-((3-iodo-1H-indazol-6-yl)methylene)-indolin-2-one except substituting 3-iodo-1H-indazole-6-carbaldehyde (462 mg, 1.70 mmol) and 1-methylindolin-2-one (250 mg, 1.70 mmol), (E)-3-((3-iodo-1H-indazol-6-yl)methylene)-1-methylindolin-2-one was obtained (yellow-orange solid, 545 mg, 80%); MS ESI 402.2 [M+H]+, calcd for [C17H12IN3O+H]+ 402.01.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][C:14]3=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[H-].[K+].[C:22](=[O:27])(OC)[O:23]C.Cl.B.[Na]>C1COCC1.ClCCl.O.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11](=[CH:10][CH:9]=2)[CH2:12][C:13]([C:22]([OH:23])=[O:27])=[CH:14]3)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C(=O)CC3)cc1
Reactant: COC(=O)OC
Agent: B
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)C3)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of 6-(4-methylphenyl)-1-indanone (4.97 g) in THF (33 ml) was dropwise added to a refluxed mixture of 60% sodium hydride (3.26 g), potassium hydride (catalytic amount), dimethyl carbonate (6.65 ml) and THF (100 ml), and the mixture was ref luxed for 6 hours. The reaction mixture was cooled to 0° C., and to the mixture was gradually added 2N hydrochloric acid (150 ml). The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/toluene=1/3) to give a brown solid. The solid was dissolved in dichloromethane (100 ml), and to the mixture was added sodium boron hydride (391 mg) at 0° C. and then was dropwise added methanol (10 ml). The reaction mixture was stirred at 0° C. for 1.5 hours, and to the mixture was added water (500 ml). The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (30 ml), and to the mixture was added 1N sodium hydroxide (40 ml). The mixture was refluxed for 2 hours and cooled to room temperature. To the mixture was added water, and the mixture was washed with diethylether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in Diglyme (30 ml), and to the mixture was added concentrated hydrochloric acid (6 ml). The mixture was stirred at 100° C. for 2 hours, and to the solution were added 0.5% sodium hydrogen carbonate solution (500 ml) and hexane(500 ml). The resulting precipitate was filtered to give 5-(4-methylphenyl)-indene-2-carboxylic acid (2.72 g) as brown crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[O:9])[CH2:4][CH2:3]1.[O:19]=[C:20]1[NH:25][C:24]2[CH:26]=[C:27]([CH:30]=O)[CH:28]=[CH:29][C:23]=2[O:22][CH2:21]1>>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][CH2:30][C:27]2[CH:28]=[CH:29][C:23]3[O:22][CH2:21][C:20](=[O:19])[NH:25][C:24]=3[CH:26]=2)[CH2:3][CH2:4]1)=[O:9]
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: NC1CCC(C(=O)c2nc3ccccc3s2)CC1
Product: O=C1COc2ccc(CN[C@H]3CC[C@H](C(=O)c4nc5ccccc5s4)CC3)cc2N1

Procedure:
The title compound was prepared according to the same protocol as for example 1, step 1.c, using however (4-amino-cyclohexyl)-benzothiazol-2-yl-methanone (0.3 mmol) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.3 mmol). 40 mg (28%) of the title compound (a yellowish solid) were obtained.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH2:24])[CH3:23])[C:19]([N:25]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:11][C:12]1[CH:21]=[C:20]([CH:22]([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:23])[C:19]([N:25]2[CH2:26][CH2:27][C:28]([F:32])([F:31])[CH2:29][CH2:30]2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(F)(F)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(F)(F)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.0244 g, 0.123 mmol), 1-[5-chloro-8-(4,4-difluoropiperidin-1-yl)quinolin-7-yl]ethanamine (0.020 g, 0.061 mmol), and N,N-diisopropylethylamine (0.021 mL, 0.12 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H21ClF2N7 (M+H)+: m/z=444.1; Found: 444.0.
Reaction SMILES: [P:1]([O:38]CC1C=CC=CC=1)([O:30]CC1C=CC=CC=1)([O:3][C:4]1[CH:9]=[C:8]([CH2:10][S:11]([CH:14]=[CH:15][C:16]2[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=2[O:26][CH3:27])(=[O:13])=[O:12])[CH:7]=[CH:6][C:5]=1[O:28][CH3:29])=[O:2].Br[Si](C)(C)C.[Na].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[P:1]([OH:38])([OH:30])([O:3][C:4]1[CH:9]=[C:8]([CH2:10][S:11](/[CH:14]=[CH:15]/[C:16]2[C:17]([O:26][CH3:27])=[CH:18][C:19]([O:24][CH3:25])=[CH:20][C:21]=2[O:22][CH3:23])(=[O:13])=[O:12])[CH:7]=[CH:6][C:5]=1[O:28][CH3:29])=[O:2]
Reactant: COc1cc(OC)c(C=CS(=O)(=O)Cc2ccc(OC)c(OP(=O)(OCc3ccccc3)OCc3ccccc3)c2)c(OC)c1
Agent: C[Si](C)(C)Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(OP(=O)(O)O)c2)c(OC)c1
Reaction time: 0.75 h
Yield: 44 %

Procedure:
To a stirred solution of 5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxy-phenyl dibenzyl phosphate (4.36 g, 6.7 mmol) in anhydrous DCM (40 mL) under nitrogen at 0° C. was added bromotrimethylsilane (2.14 g, 2.1 eq). The resulting mixture was stirred for 45 minutes and monitored by TLC. sodium When the reaction was complete, aqueous sodium thiosulfate (1%, 50 mL) was added and the resulting mixture was stirred for an additional 5 minutes. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic extract was concentrated in vacuo to afford the crude 5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxyphenyl dihydrogen phosphate. The product was purified column chromatography on silica eluted with a methanol/chloroform gradient to yield 1.4 g of the purified product having a melting point of 202-205° C.