Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH:28]([CH3:32])[CH2:29][C:30]=4[N:31]=3)=[O:22])[CH:17]([C:33]([O:35]CC)=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(O)C.[OH-].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH:28]([CH3:32])[CH2:29][C:30]=4[N:31]=3)=[O:22])[CH:17]([C:33]([OH:35])=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)O)sc2CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In tetrahydrofuran (10 ml), 4-[(6-chloronaphthalen-2-yl)sulfonyl]-2-(ethoxycarbonyl)-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine (2.08 g) was dissolved, followed by the addition of ethanol (20 ml) and a 1N aqueous solution (3.70 ml) of sodium hydroxide. The resulting mixture was stirred at room temperature for 1 hour. After concentration of the reaction mixture under reduced pressure, the residue was added with water (20 ml). The precipitate thus formed was collected by filtration, whereby the title compound (1.39 g) was obtained as a pale yellow foam.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[N:22]3[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]3)=[C:16](Br)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.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>[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36]([C:16]3[CH:15]=[C:14]([CH:10]4[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:9]4)[N:22]4[C:17]=3[C:18]([NH2:23])=[N:19][CH:20]=[N:21]4)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ncnn2c(C3CN(Cc4ccccc4)CCO3)cc(Br)c12
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnn2c(C3CN(Cc4ccccc4)CCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A stirred, degassed mixture of 7-(4-benzylmorpholin-2-yl)-5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (701 mg, 1.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (350 mg, 0.30 mmol) in DMF (2 mL) was stirred under N2 for 30 min at 80 C, then treated with 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (754 mg, 2.26 mmol), K3PO4 (765 mg, 3.61 mmol) and H2O (165 mg, 9 mmol). The reaction was heated (100° C.) for 1 h and then cooled to rt. The mixture was partitioned between ethyl acetate (25 mL) and MeOH (2.5 mL) and the mixture filtered through a long silica plug. After removal of the volatiles in vacuo, the residue was purified by ISCO® chromatography using a gradient of 1% to 10% MeOH in CH2Cl2 to afford 401 mg (43%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.79 (d, 1 H, J=9 Hz), 7.57 (s, 1 H), 7.21-7.38 (m, 5 H), 7:12 (d, 1 H, J=9 Hz), 6.73 (s, 1 H), 5.65 (s, 2 H), 5.10 (dd, 1H, J=10, 2Hz), 3.88 (d, 1H, J=12 Hz), 3.69 (dd, 1H, J=10, 9 Hz), 3.57 (d, 1H, J=13 Hz), 3.51 (d, 1H, J=13 Hz), 2.97 (d, 1H, J=12 Hz), 2.17-2.28 (m, 1H), 2.67 (d, 1H, J=11 Hz), 2.36 (t, 1H, J=11 Hz); ES-MS m/z 516.3 [M+H]+, HPLC RT (min) 2.80.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:8]2[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].CO[Na].[C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Br)#[N:27]>CS(C)=O>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[C:26]#[N:27])=[CH:18][CH:17]=2)[C:8]2[C:9](=[O:13])[NH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(O)cc1
Reactant: N#Cc1ccccc1CBr
Agent: CO[Na]
Solvent: CS(C)=O
Product: CCCCc1nc2cc[nH]c(=O)c2n1Cc1ccc(OCc2ccccc2C#N)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 2.97 g of 2-butyl-3-p-hydroxybenzyl-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine (obtainable from IIIa and p-hydroxybenzyl bromide), 0.5 g of CH3ONa and 40 ml of DMSO is stirred for 0.5 hour. A solution of 2.2 g of o-cyanobenzyl bromide in 15 ml of DMSO is added dropwise and the mixture is stirred at 20° for 16 hours and evaporated to give 2-butyl-3-(4-o-cyanobenzyloxybenzyl)-4,5-dihydro-4-oxo-3H-imidazo[4,5-c]pyridine after conventional working-up.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:35][NH:36][CH2:37][CH:38]([OH:46])[C:39]1[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:36]([CH2:37][CH:38]([OH:46])[C:39]4[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=4)[CH3:35])[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Reactant: CNCC(O)c1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(Cc1ccc2c(c1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)CC(O)c1ccc(O)cc1
Reaction time: 8 h
Yield: 74.2 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.09 gm) from Preparation No. 35 in dry DMF (2 mL) containing diisopropylethylamine (0.07 mL) is treated with synephrine (0.05 gm). The reaction mixture is stirred overnight. The reaction mixture is diluted with dichloromethane (50 mL) and washed with water (2×10 mL), brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue is purified by flash column chromatography eluting with 3% to 6% methanol in dichloromethane and then by recrystallization from toluene to afford 0.09 gm of the title compound as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([O:24]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[C].[Pd]>[CH2:20]([O:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:24])[CH:16]=2)[C:11](=[O:32])[N:10]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:9]=1[CH2:8][NH:7][C:6](=[O:37])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A suspension of tert-butyl(6-benzyloxy-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (6.10 g, 12 mmol) and 5% palladium carbon (2.0 g) in tetrahydrofuran (30 mL) and ethanol (30 mL) was stirred under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl (4-butoxy-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (4.86 g, 96.8%) as crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:18][CH:17](OS(C)(=O)=O)[CH2:16]2)[S:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([S:26][CH:17]1[CH2:16][N:15]([C:12]2[S:13][CH:14]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[N:11]=2)[CH2:18]1)(=[O:27])[CH3:25]
Reactant: CC([O-])=S
Reactant: CC(C)(C)[Si](C)(C)OCc1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CO[Si](C)(C)C(C)(C)C)cs2)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a solution of 1-(4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (326.5 mg, 0.86 mmol) (obtained as described in Reference Example 12(3)) in dimethylformamide (16 ml) was added potassium thioacetate (780 mg, 5.41 mmol) at room temperature, and the reaction mixture was then stirred in an oil bath (80° C.) for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1) as the eluant to afford 3-acetylthio-1-(4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl)azetidine (191 mg, yield 62%) as a brown syrup.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9][CH2:8]2)[C:5]2[CH:21]=[CH:22][C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:24][C:4]=2[N:3]=1.[Br:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[N:35]=[C:34]2I.O1CCOCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[N:35]=[C:34]2[NH:1][C:2]1[N:6]([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:9][CH2:8]2)[C:5]2[CH:21]=[CH:22][C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:24][C:4]=2[N:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)ccc21
Reactant: CCOC(=O)c1ccc2c(c1)nc(N)n2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(c1)nc(Nc1nn(COCC[Si](C)(C)C)c3ccc(Br)cc13)n2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1

Procedure:
A mixture of ethyl 2-amino-1-(trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)-1H-benzo[d]imidazole-5-carboxylate (102 mg, 0.000244 mol), 5-bromo-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (130 mg, 0.00029 mol), 1,4-dioxane (0.6 mL, 0.007 mol), potassium phosphate (78 mg, 0.00037 mol), xantphos (34 mg, 0.000059 mol) and tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.00002 mol) was placed in a microwave reaction vessel. The reaction mixture was stirred under nitrogen and the sides were washed down with additional 1,4-dioxane (0.5 mL). The reaction vessel was irradiated under microwave radiation for 60 minutes at 130° C. The reaction mixture was diluted with ethyl acetate and washed with aqueous saturated sodium bicarbonate and then brine. The organic phase was dried over sodium sulfate and concentrated to a brown residue which was purified by combiflash chromatography on a 40 g silica gel cartridge using an initial eluent of 10% ethyl acetate-90% hexanes for 5 minutes then a gradient to 30% ethyl acetate over the next 15 minutes. Concentration of the product fractions gave a yellow oil (99.1 mg).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]1[CH2:32][O:31][C:10]2([CH2:15][CH2:14][C@H:13]3[C@H:16]4[C@H:25]([CH2:26][CH2:27][C@:11]23[CH3:12])[C:24]2[CH:23]=[C:22]([O:28][CH3:29])C(O)=C[C:19]=2[CH2:18][CH2:17]4)[O:9]1.N1C=CC=CC=1>CO>[C:5]([O:4][C:1]1[C:22]([O:28][CH3:29])=[CH:23][C:24]2[C@@H:25]3[C@H:16]([C@H:13]4[C@@:11]([CH2:27][CH2:26]3)([CH3:12])[C:10]3([O:9][CH2:8][CH2:32][O:31]3)[CH2:15][CH2:14]4)[CH2:17][CH2:18][C:19]=2[CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Solvent: c1ccncc1
Solvent: CO
Product: COc1cc2c(cc1OC(C)=O)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
Under nitrogen, acetic anhydride (25 mL, 265 mmol) was added to a solution of the ketal (11) (4.5 g, 13.06 mmol) in dry pyridine (25 mL, 310 mmol). The reaction was stirred overnight at room temperature in the dark. After that time, methanol (50 mL) was added and solvents removed in vacuo. The treatment with methanol was repeated and the residue obtained crystallized from methanol to give the pure 3-acetate (12) (4.85 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH2:7]([O:9][CH:10](OCC)OCC)[CH3:8]>CCCCCC>[CH2:7]([O:9][CH:10]=[N:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1)[CH3:8]
Reactant: CCOC(OCC)OCC
Reactant: Nc1nnn[nH]1
Solvent: CCCCCC
Product: CCOC=Nc1nnn[nH]1
Temperature: 25 °C

Procedure:
A mixture was prepared from 50 g of 5-aminotetrazole, 347 g of triethoxymethane and 500 ml of hexane and this was heated under nitrogen so that distillation took place at a moderate rate (head temperature about 60°-68° C.). Distillate was collected over a period of 6 hours with hexane being replaced in the reaction mixture as necessary. The mixture was then cooled to room temperature and the fine white needles that formed were collected by filtration, washed with hexane and vacuum oven dried with heating to give 5-(ethoxymethyleneamino)tetrazole. This material hydrolyzes rapidly on exposure to atmospheric moisture so that it should be used promptly for any further reactions desired or it should be stored using appropriate conditions.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH2:50]([N:52]([CH:56]1[CH2:60][CH2:59][NH:58][CH2:57]1)[C:53](=[O:55])[CH3:54])[CH3:51]>>[C:28]([C:32]1[N:33]=[C:34]([N:58]2[CH2:59][CH2:60][CH:56]([N:52]([CH2:50][CH3:51])[C:53](=[O:55])[CH3:54])[CH2:57]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CCN(C(C)=O)C1CCNC1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: CCN(C(C)=O)C1CCN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and N-ethyl-N-(pyrrolidin-3-yl)acetamide. MS(m/e): 456.5 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:32])/[CH:17]=[CH:18]/[CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].C(O)C.[H][H]>[Pt]=O.O1CCOCC1>[CH3:1][C:2]1[C:3]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:32])[CH2:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:23][CH2:24]3)=[CH:14][CH:15]=2)=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ncnc(Nc2ccc(C(=O)/C=C/C3CCN(Cc4ccccc4)CC3)cc2)c1C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ncnc(Nc2ccc(C(=O)CCC3CCN(Cc4ccccc4)CC3)cc2)c1C
Yield: 47.3 %

Procedure:
0.82 g of (E)-N-(5,6-dimethylpyrimidin-4-yl)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline obtained in Example 1 was added to a mixed solvent of 30 ml of ethanol and 40 ml of dioxane, and then 0.05 g of platinum oxide was added thereto. The mixture was stirred in a hydrogen stream at room temperature for 3.5 hours. After the catalyst was removed by filtration, the filtrate was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.39 g of the title compound as pale yellow powder.
Reaction SMILES: [ClH:1].O1CCOCC1.[C:8]([C:10]1[N:14]2[CH2:15][CH2:16][N:17]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:18]3([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:13]2=[CH:12][CH:11]=1)#[N:9]>ClCCl>[ClH:1].[C:8]([C:10]1[N:14]2[CH2:15][CH2:16][N:17]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:18]3([CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)[C:13]2=[CH:12][CH:11]=1)#[N:9]
Reactant: CCOC(=O)N1CCn2c(C#N)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)N1CCn2c(C#N)ccc2C12CCNCC2
Temperature: 40 °C
Reaction time: 1 h

Procedure:
4 N HCl in dioxane (8.7 mL, 34.7 mmol) was added to a solution of 1-tert-butyl 2′-ethyl 6′-cyano-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-1,2′-dicarboxylate (0.27 mmol) in dichloromethane (5 mL) and the mixture was stirred at 40° C. for 1 hour. The reaction mixture was evaporated to dryness to give ethyl 6′-cyano-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-2′-carboxylate hydrochloride. ESI-MS m/z calc. 288.2, found 289.3 (M+1)+; Retention time: 0.75 minutes (3 minute run).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8].[C:14]1([Si:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>N1C=CC=CC=1>[C:27]1([Si:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]2=[O:8])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=c1ccn(CCCCO)c(=O)[nH]1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CO
Product: O=c1ccn(CCCCO[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Reaction time: 2 h

Procedure:
1-(4′-Hydroxybutyl)uracil (0.048 g, 0.26 mmol) was dissolved in dry pyridine (1.5 mL) and cooled in an ice-salt bath. A solution of triphenylsilyl chloride (0.099 g, 0.34 mmol) in dry pyridine (1.5 mL) was added drop-wise. The reaction mixture was kept at 0° C. under nitrogen for 2 h 30. CH3OH (15 μL) was added and after 10 min the solution was concentrated on the rotary evaporator. The resultant crude transparent oil was purified by silica gel chromatography using a gradient elution of 0→3% CH3OH in CHCl3. The title compound was obtained as a white solid (0.085 g, 74%) from the fractions with Rf=0.50 (10% CH3OH/CHCl3).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][C:33]1[S:34][C:35]2[CH:41]=[C:40]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:38][C:36]=2[N:37]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:40]1[CH:39]=[CH:38][C:36]2[N:37]=[C:33]([CH3:32])[S:34][C:35]=2[CH:41]=1)(=[O:43])=[O:44]
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc2ccc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5c4ncn5C4CCCCO4)c3F)cc2s1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2-methylbenzo[d]thiazole-6-sulfonyl chloride (17 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1>[N+:8]([C:7]1[C:2]([C:16]2[CH:17]=[CH:18][C:13]([CH:11]=[CH2:12])=[CH:14][CH:15]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2ncccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
2-Chloro-3-nitropyridine (4.37 g, 27.6 mmol), 4-vinylphenylboronic acid (4.5 g, 30.4 mmol), tetrakis(triphenylphosphine)palladium (0) (3.19 g, 2.8 mmol), and potassium carbonate (11.4 g, 82.8 mmol) were added to anhydrous 1,4-dioxane (60 ml). The reaction mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature, filtered with a Celite pad, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography and then crystallized with ethyl ether to give 4.9 g of the titled compound as a white solid. (Yield: 79%) The product was used in the subsequent step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][NH:24][CH3:25]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:25])[CH3:23])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CNC
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CN(C)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and Dimethylamine were converted to yield [4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-dimethyl-amine as white semisolid, MS: 405(MH+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH2:29][NH2:30].[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:30][CH2:29][C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)=[CH:17][CH:16]=1
Reactant: NCc1cccs1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CNCc2cccs2)cc1
Yield: 70.4 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-((thiophen-2-ylmethylamino)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.100 g; 0.288 mmol), thiophen-2-ylmethanamine (0.138 mL; 1.30 mmol) and sodium iodide (0.218 g; 1.44 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 2 to 10% methanol in dichloromethane) furnished 0.086 g (71%) of the title compound as a white solid.