Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH-].[Na+].[CH2:4]([O:11][C:12]1[CH:27]=[CH:26][C:15]([C:16](Cl)(C(C)(C)C)C(C)(C)C)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=[N:35][C:36]1[N:37]=[CH:38][NH:39][C:40]=1[C:41]([NH2:43])=[O:42])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:35][C:36]1[N:37]=[CH:38][N:39]([CH2:16][C:15]2[CH:14]=[C:13]([C:5]([CH3:10])([CH3:6])[CH3:4])[C:12]([O:11][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[C:27]([C:15]([CH3:26])([CH3:16])[CH3:14])[CH:26]=2)[C:40]=1[C:41]([NH2:43])=[O:42]
Reactant: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Reactant: CC(C)(C)C(Cl)(c1ccc(OCc2ccccc2)cc1)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Cn2cnc(N)c2C(N)=O)cc(C(C)(C)C)c1OCc1ccccc1
Yield: 77 %

Procedure:
The benzylidation reaction in N,N-dimethylformamide-distilled water, benzylidene de-protection reaction with hydrochloric acid, and neutralization reaction of hydrochloride with sodium hydroxide were carried out in the same manner as in Example 71, using the benzyl chloride, 1.95 g (9.1 mmol) of 4-benzylideneamino-5-imidazolecarboxamide, and 5.03 g (36.4 mmol) of potassium carbonate, to obtain 2.44 g of 4-amino-1-(4-benzyloxy-3,5-di-t-butylbenzyl)-5-imidazolecarboxamide (yield 77%).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15]([C:17]2[C:18]([O:23][C:24]3[CH:32]=[CH:31][C:27]4[O:28][CH2:29][O:30][C:26]=4[CH:25]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[C:9]([F:33])[CH:8]=1)[CH3:5].COC(=O)COC1C=CC(CNC(C2C(OC3C=CC4OCOC=4C=3)=NC=CC=2)=O)=C(F)C=1>>[O:28]1[C:27]2[CH:31]=[CH:32][C:24]([O:23][C:18]3[C:17]([C:15]([NH:14][CH2:13][C:10]4[CH:11]=[CH:12][C:7]([O:6][C@H:4]([CH3:5])[C:3]([OH:34])=[O:2])=[CH:8][C:9]=4[F:33])=[O:16])=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:25][C:26]=2[O:30][CH2:29]1
Reactant: COC(=O)[C@@H](C)Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Agent: COC(=O)COc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O

Procedure:
The compound of Formula (5.5.8) was prepared in a manner analogous to that described in Example 1, substituting (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid methyl ester for the corresponding [4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-acetic acid methyl ester material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[O:5][CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[O:5][CH:6]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:26][CH:25]=2)=[CH:17][CH:18]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccc(F)c(F)c2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 92.3 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(3,4-difluorophenoxy)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (281 mg), which is the product of Example 140, was reacted with aqueous sodium hydroxide solution (1N, 1.02 ml) and the reaction mixture was treated to give the title compound (246 mg) as a white powder.
Reaction SMILES: [CH:1]1([S:7]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]1([NH:15][S:16]([C:19]2[S:20][C:21]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:22]=3[N:23]=2)(=[O:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C.C(Cl)(Cl)Cl>CN(C)C=O>[CH:1]1([S:7][N:15]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[S:16]([C:19]2[S:20][C:21]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:22]=3[N:23]=2)(=[O:17])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(NC1CCCCC1)c1nc2cc(Cl)ccc2s1
Reactant: ClSC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1nc2cc(Cl)ccc2s1)N(SC1CCCCC1)C1CCCCC1
Temperature: 0 °C

Procedure:
2.6 grams of cyclohexyl chlorosulfide (0.0172 mole) prepared as in Example 1 is added slowly to a stirred solution containing 5.4 grams (0.0163 mole) of N-cyclohexyl-5-chlorobenzothiazole-2-sulfonamide, and 2 grams of triethylamine (0.0178 mole) in 150 ml anhydrous dimethylformamide. The temperature is maintained between about 15° and 20° C. After stirring, 100 ml of chloroform is added and the reaction mixture is poured into 2 liters of ice water, and treated as in Example 5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][C:15]=2[CH:26]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:29]([NH2:31])[CH3:30]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][C:15]=2[CH2:26][NH:31][CH2:29][CH3:30])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3cnn(C)c3)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(-c2cnn(C)c2)ccc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using the following starting materials: [2′-formyl-6-methoxy-4′-(1-methyl-1H-pyrazol-4-yl)-biphenyl-3-yl]-acetic acid ethyl ester and ethylamine (2M in THF).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].[Cl:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:25][C:26]1[N:31]=[C:30]([NH:1][CH2:2][C@H:3]2[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])[CH:29]=[CH:28][N:27]=1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccnc(Cl)n2)c(-c2ccc(F)cc2)s1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2,4-dichloropyrimidine, and K2CO3 in DMAC was stirred at 120° C. for 18 h. The reaction was cooled and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound as the major isomer. MS (ESI) 459.94 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[O:21]=[C:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[CH2:29][CH2:30][CH:31]=O>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:31][CH2:30][CH2:29][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:22]3=[O:21])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: O=CCCN1CCCCCC1=O
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCN1CCCCCC1=O

Procedure:
This compound was prepared from ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate and 3-(2-oxohexahydro-1H-azepin-1-yl)propanal using methods similar to Example 669: step 4 to provide a clear oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (t, J=7.09 Hz, 3 H), 1.47-1.58 (m, 4 H), 1.58-1.74 (m, 4 H), 2.36-2.44 (m, 2 H), 3.15 (q, J=6.74 Hz, 2 H), 3.28-3.38 (m, 4 H), 3.94 (s, 2 H), 4.26 (q, J=7.07 Hz, 2 H), 7.07-7.16 (m, 3 H), 7.27-7.34 (m, 2 H), 7.62 (t, J=5.62 Hz, 1 H), 7.77 (d, J=1.82 Hz, 1 H); ES+ MS: 428 (M+H+).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:31])[CH2:28][CH2:29][CH3:30]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:31])[CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CCCC(=O)O
Agent: Cl
Product: CCCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (76 mg, 77%), MS (ISP) m/z=399.3 [(M+H)+], mp 196° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and butyric acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].O1CC[CH2:34][CH2:33]1.C(I)C>CN(C)C=O>[CH2:33]([O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2)[CH3:34]
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O)c2[nH]1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)OC)[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To an ice-cooled and stirred solution of methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.2 g) and potassium carbonate (0.50 g) in N,N-dimethylformamide (10 mL)-tetrahydrofuran (30 mL) was added ethyl iodide (0.28 mL), and the mixture was stirred at room temperature for 18 h and then at 55° C. for 15 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed successively with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=25:75 to 40:60, volume ratio) to give the title compound (0.65 g, 50%) as light yellow crystals. MS 391 (MH+).
Reaction SMILES: C(C1N=[C:12]([OH:14])[CH:11]=[C:10]([OH:15])N=1)C1C=CC=CC=1.Cl.[CH2:17]([S:19][CH:20]([S:24][CH2:25][CH3:26])[C:21]([NH2:23])=[NH:22])[CH3:18].C(OCC)(=O)CC(OCC)=O>>[CH2:17]([S:19][CH:20]([S:24][CH2:25][CH3:26])[C:21]1[N:23]=[C:12]([OH:14])[CH:11]=[C:10]([OH:15])[N:22]=1)[CH3:18]
Reactant: CCSC(SCC)C(=N)N
Reactant: Oc1cc(O)nc(Cc2ccccc2)n1
Agent: Cl
Solvent: CCOC(=O)CC(=O)OCC
Product: CCSC(SCC)c1nc(O)cc(O)n1

Procedure:
Prepared in a manner similar to 2-benzylpyrimidine-4,6-diol using 2,2-bis(ethylthio)acetamidine hydrochloride 4 and diethyl malonate as the starting materials to yield a dark yellow waxy solid. MS: (ESI, Neg) m/z 245.3 (M−1). H1 NMR: 11.7 ppm (d) 2H. 5.2 ppm (s) 0.69H. 4.8 ppm (s) 1H. 2.65 ppm (m) 4H. 1.17 ppm (t) 6H. Subsequent sulfanyl oxidation can be used to generate various Y moieties, C(O), etc., as described above.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(NCC(C)C)C(C)C.S(Cl)([Cl:25])(=O)=O>C1(C)C=CC=CC=1>[Cl:25][C:10]1[CH:11]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1ccc(C2CCCC2)cc1
Agent: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Product: Oc1ccc(C2CCCC2)cc1Cl
Temperature: 25 °C

Procedure:
A solution of 4-cyclopentylphenol (4 g) and diisobutylamine (0.35 mL) in toluene (75 mL) was heated to 70° C. with stirring. Sulfuryl chloride (2.0 mL) was introduced via syringe and the reaction stirred for 2 h at 70° C., then cooled to room temperature. The reaction mixture was concentrated in vacuo and the resulting oil subjected to chromatography on silica gel using hexane/ethyl acetate eluent to afford the title compound (3.5 g). 1H NMR (400 MHz, CDCl3): δ 7.19 (d, 1H, J=2.0 Hz); 7.06 (dd, 1H, J=2.2 Hz, 6.2 Hz); 6.94 (d, 1H, J=8.6 Hz); 5.37 (s, 1H); 2.92 (quint, 1H, J=7.0 Hz); 2.03 (m, 2H); 1.80 (m, 2H); 1.67 (m, 2H); 1.53 (m, 2H). MS: m/e=197(M+).
Reaction SMILES: C1(=O)N(CS(Cl)(=O)=O)C(=O)C2=CC=CC=C12.C1(=O)N(CCS(Cl)(=O)=O)C(=O)C2=CC=CC=C12.C(NS(CN1C(=O)C2=CC=CC=C2C1=O)(=O)=O)(C)(C)C.C([NH:58][S:59]([CH2:62][N:63]1[C:67]([SH:68])=[N:66][N:65]=[N:64]1)(=[O:61])=[O:60])(C)(C)C.FC(F)(F)C(O)=O>>[S:59]([CH2:62][N:63]1[C:67]([SH:68])=[N:66][N:65]=[N:64]1)(=[O:61])(=[O:60])[NH2:58]
Reactant: CC(C)(C)NS(=O)(=O)Cn1nnnc1S
Agent: CC(C)(C)NS(=O)(=O)CN1C(=O)c2ccccc2C1=O
Agent: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Agent: O=C1c2ccccc2C(=O)N1CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)Cn1nnnc1S

Procedure:
When phthalimidomethanesulfonyl chloride is substituted in the procedure of Example 3 for 2-phthalimidoethanesulfonyl chloride, N-t-butylphthalimidomethanesulfonamide is prepared which is converted to 1-N-t-butylsulfamoylmethyltetrazole-5-thiol as described therein. Treatment of 1-N-t-butylsulfamoylmethyltetrazole-5-thiol with trifluoroacetic acid as described in Example 3 gives 1-sulfamoylmethyltetrazole-5-thiol.
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:61][CH3:62])[N:32]2[CH2:42][CH2:43][CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][N:47](C(OCC2C=CC=CC=2)=O)[CH2:46]1>>[CH2:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:61][CH3:62])[N:32]2[CH2:42][CH2:43][CH2:44][CH:45]2[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 3-{3-[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]propyl}-1-piperidinecarboxylate.
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH:8]([CH3:10])[CH3:9])[C:3](OCC)=[O:4].Cl.[NH2:13][C:14](N)=[NH:15].C([O-])([O-])=O.[K+].[K+]>C(O)C>[NH2:15][C:14]1[O:1][C:2]([CH:8]([CH3:10])[CH3:9])([CH3:11])[C:3](=[O:4])[N:13]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(C)(O)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)C1(C)OC(N)=NC1=O

Procedure:
A mixture of ethyl 2-hydroxy-2,3-dimethylbutanoate (2.92 g, 18.2 mmol), guanidine hydrochloride (1.74 g, 18.2 mmol), and K2CO3 (2.52 g, 18.2 mmol) in 99.5% ethanol (40 mL) was stirred under reflux for 20 h. The solvent was removed, and the residue was purified by silica gel flash chromatography (ethyl acetate/methanol 9:1) to give the product as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[C:42]3[C:38]([CH:39]=[N:40][NH:41]3)=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:43]=[C:42]3[C:38]([CH:39]=[N:40][NH:41]3)=[CH:37][CH:36]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc3cn[nH]c3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4cn[nH]c4c3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 from 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (59.4 mg, 0.243 mmol), DMSO(1.5 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 55 mg (65%). LCMS E-S (M+H)=456.0 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.65 (m, J=6.4 Hz, 6 H), 2.14 (s, 3 H), 2.23 (s, 3 H), 4.43 (d, J=4.6 Hz, 2 H), 5.36 (quin, J=6.7 Hz, 1 H), 5.87-5.97 (m, 1 H), 7.52-7.72 (m, 2 H) 7.92 (d, J=8.6 Hz, 1 H), 8.08 (d, J=8.6 Hz, 1 H), 8.16 (s, 1 H), 8.26 (s, 1 H), 8.37-8.49 (m, 2 H), 8.96-9.14 (m, 1 H), 11.59 (br. s., 1 H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C:6]([CH2:16][CH3:17])([CH2:14][CH3:15])[N:5]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:4]=2[N:3]=1.C[CH:24]1[CH2:28][C:27]2=[C:29]([C:34]([OH:36])=[O:35])[CH:30]=[CH:31][C:32]([NH2:33])=[C:26]2[O:25]1.Cl>C(O)C.O>[CH:18]1([N:5]2[C:4]3[N:3]=[C:2]([NH:33][C:32]4[CH:31]=[CH:30][C:29]([C:34]([OH:36])=[O:35])=[C:27]5[C:26]=4[O:25][CH2:24][CH2:28]5)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C:6]2([CH2:16][CH3:17])[CH2:14][CH3:15])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC1Cc2c(C(=O)O)ccc(N)c2O1
Reactant: CCC1(CC)C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCC1(CC)C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Yield: 38.4 %

Procedure:
2-Chloro-8-cyclopentyl-7,7-diethyl-5-methyl-pteridin-6-one 42a (100 mg, 0.31 mmol) and methyl 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid 1g (50 mg, 0.28 mmol) were dissolved in 17 mL of the mixture solvent of ethanol and water (V/V=5:12) followed by the addition of 0.2 mL of concentrated hydrochloric acid. The reaction mixture was heated to reflux for 16 hours with stirring. The resulting solution was concentrated under reduced pressure, added dropwise with 1 M lithium hydroxide solution to adjust pH to 12 and extracted with ethyl acetate (50 mL×2), the combined aqueous phase was added dropwise with 1 M hydrochloric acid to adjust pH to 1 and extracted with dichloromethane (50 mL×3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain 7-[(8-cyclopentyl-7,7-diethyl-5-methyl-6-oxo-pteridin-2-yl)amino]-2,3-dihydrobenzofuran-4-carboxylic acid 42b (50 mg, yield: 38.0%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([CH2:18][CH2:19]Cl)(=[O:17])=[O:16])=[CH:10][CH:9]=1)(=[O:6])=[O:5].C(N(CC)CC)C.C1(C=CC(O)=CC=1)O>C(OCC)(=O)C.CN(C)C=O>[CH:18]([S:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])=[CH:9][CH:10]=1)(=[O:17])=[O:16])=[CH2:19]
Reactant: O=S(=O)(CCCl)Cc1ccc(CS(=O)(=O)CCCl)cc1
Agent: Oc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CS(=O)(=O)Cc1ccc(CS(=O)(=O)C=C)cc1

Procedure:
A suspension consisting of 21.2 g. of α,α'-bis(2-chloroethylsulfonyl)-p-xylene (prepared from p-xylylene dichloride as in Example 1), 25 ml. of triethylamine, 0.05 g. of hydroquinone and 400 ml. of ethyl acetate-N,N-dimethylformamide (1:1 v./v.) were stirred at 25° C. for 20 hours and filtered. The filtrate was evaporated to 150 ml. volume, poured into water and the white solid isolated and recrystallized from methanol and ethyl acetate; m.p. 207°-212° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH2:7].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12]>O>[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH:7][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: COC(CN)OC
Reactant: C=C(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)C(=O)NCC(OC)OC
Temperature: -10 °C
Yield: 82.4 %

Procedure:
220 g (5.5 mol) of sodium hydroxide are dissolved in 300 g of water and 700 g of ice in a 3-litre reactor having a stirrer and a cooling system. The sodium hydroxide solution is cooled to 10° C. and 526 g (5.0 mol) of aminoacetaldehyde dimethylacetal and 50 mg of 4-hydroxy-2,2,6,-tetramethylpiperidin-1-oxide (radical inhibitor) are added. 548.6 g (5.5 mol) of methacrylic acid chloride are slowly added at 10° C. to the solution over a period of 3.5 hours. When the addition is complete, the pH value drops slowly to 7.2 and amine can no longer be detected by GC. The reaction mixture is extracted with 500 ml of petroleum ether, and in order to remove impurities, the aqueous phase is saturated with sodium chloride and extracted three times with 500 ml of tert-butyl methyl ether. The organic phase is dried with magnesium sulfate, filtered and concentrated using a rotary evaporator. The resulting 882.2 g of yellowish oil are slowly stirred into 2000 ml of petroleum ether at -10° C. by means of an Ultraturax. The product crystallises, and is isolated by filtration and dried. 713.8 g of methacrylamidoacetaldehyde dimethylacetal (86% of theory), melting point 30°-32° C., are obtained; the product is 99.7% according to GC.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(C)ccc4nc3OC)CC2)c1
Yield: 73 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 73%). 1H NMR (300 MHz, CDCl3): δ 2.43-2.48 (m, 3H), 3.23-3.30 (m, 4H), 3.76-3.87 (m, 3H), 4.04-4.13 (m, 4H), 6.45-6.50 (m, 2H), 6.57 (d, J=8.4 Hz, 1H), 7.01-7.12 (m, 1H), 7.17-7.33 (m, 3H), 7.48-7.65 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C:5]2[CH:7]=[C:8]3[O:12][C:11]([CH3:14])([CH3:13])[O:10][C:9]3=[CH:15][C:4]=2[O:3]1.C([Li])CCC.[CH3:22][C:23]1([CH3:55])[O:27][C:26]2[C:28]([C:37]([C:39]3[C:49]4[O:50][C:51]([CH3:54])([CH3:53])[O:52][C:48]=4[CH:47]=[C:41]4[O:42][C:43]([CH3:46])([CH3:45])[O:44][C:40]=34)=[O:38])=[C:29]3[O:33][C:32]([CH3:35])([CH3:34])[O:31][C:30]3=[CH:36][C:25]=2[O:24]1>C1COCC1>[CH3:13][C:11]1([CH3:14])[O:10][C:9]2[C:15]([C:37]([C:28]3[C:26]4[O:27][C:23]([CH3:55])([CH3:22])[O:24][C:25]=4[CH:36]=[C:30]4[O:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=34)([C:39]3[C:49]4[O:50][C:51]([CH3:53])([CH3:54])[O:52][C:48]=4[CH:47]=[C:41]4[O:42][C:43]([CH3:45])([CH3:46])[O:44][C:40]=34)[OH:38])=[C:4]3[O:3][C:2]([CH3:16])([CH3:1])[O:6][C:5]3=[CH:7][C:8]=2[O:12]1
Reactant: CC1(C)Oc2cc3c(c(C(=O)c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c2O1)OC(C)(C)O3
Reactant: CC1(C)Oc2cc3c(cc2O1)OC(C)(C)O3
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Oc2cc3c(c(C(O)(c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c4c5c(cc6c4OC(C)(C)O6)OC(C)(C)O5)c2O1)OC(C)(C)O3
Reaction time: 0.5 h

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole (8.80 g, 40.00 mmol, Example 5) was dissolved in THF (100 mL) and cooled to -20° C. n-Butyllithium (25.0 mL, 40.0 mmol, 1.6M) was added and the temperature was adjusted to ambient temperature over a period of 30 minutes and then recooled to -20° C. Bis(2,2,6,6-tetramethylbenzo-(1,2-d:4,5-d']bis(1,3)dioxole-4-yl)ketone (18.80 g, 39.83 mmol, Example 57) was added and the temperature was once more adjusted to room temperature and the mixture was stirred for 18 hours. The mixture was then poured on water/AcOH (100 mL, 2% AcOH) and extracted with diethyl ether (2×100 mL). The organic phase was washed with water (2×100 ml) and dried (Na2SO4). The solvent was evaporated and the product was washed with petroleum ether (20 mL, 40-60° C.). Yield 10.80 g (64.1%). Spectral data see example 44.