Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][OH:30])=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16].O[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[O:48][C:47]([CH:49]=[O:50])=[CH:46][CH:45]=2)=[CH:40][C:39]=1[CH3:51].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:15]([N:17]1[C:23]2[N:24]=[CH:25][C:26]([CH2:28][CH2:29][O:30][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[O:48][C:47]([CH:49]=[O:50])=[CH:46][CH:45]=4)=[CH:40][C:39]=3[CH3:51])=[CH:27][C:22]=2[C:21](=[O:31])[N:20]([CH3:32])[C:19]2[CH:33]=[CH:34][CH:35]=[N:36][C:18]1=2)[CH3:16]
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2cccnc21
Reactant: Cc1cc(-c2ccc(C=O)o2)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccc(-c4ccc(C=O)o4)cc3C)cc2C(=O)N(C)c2cccnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
DIAD (107 μL, 0.54 mmol) was added dropwise to a solution of 11-ethyl-5,11-dihydro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (135 mg, 0.45 mmol), 5-(4-hydroxy-3-methylphenyl)-2-furanecarboxaldehyde (110 mg, 0.54 mmol) and PPh3 (143 mg, 0.54 mmol) in THF (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 3:2) to give the title compound (147 mg, 67% yield) as a pale yellow foam.
Reaction SMILES: [CH:1]1([CH:6]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]1([CH:6]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:7]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Ethyl 3-{[(4-{[cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (363 mg) synthesized in Example A189 was dissolved in ethanol (1.5 mL) and tetrahydrofuran (1.5 mL), 1N aqueous sodium hydroxide solution (1.5 mL) was added to the solution, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 mL) was added to the mixture, and the mixture was neutralized with 1N hydrochloric acid under ice-cooling, and the mixture was stirred for 30 min. The resulting precipitate was collected by filtration, and dried to give the title compound (283 mg, 83%) as a colorless solid.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8].[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][CH2:20][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:6]=1[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: COC(=O)CCC(=O)c1ccc(C)cc1OCC1CO1
Product: COC(=O)CCC(=O)c1ccc(C)cc1OCC(O)CNC(C)(C)C

Procedure:
Methyl 3-[2-(2,3-epoxypropoxy)-4-methylbenzoyl]-propionate was treated with t-butylamine in a similar manner to the procedure described in Example 2(i) to give methyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methylbenzoyl]-propionate, m.p. 82°-84.5°.
Reaction SMILES: Br[Zn][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[C:12]1[C:21]2[C:16](=[C:17]([C:22]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[C:29]([Cl:37])[CH:28]=4)[O:24][N:23]=3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>C1COCC1.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>[Cl:37][C:29]1[CH:28]=[C:27]([C:25]2[O:24][N:23]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:16]=3[CH:15]=[CH:14][N:13]=[C:12]4[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:26]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Br)nccc34)no2)cc1Cl
Reactant: CCOC(=O)CCC[Zn]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1nccc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12

Procedure:
Bromo[4-(ethyloxy)-4-oxobutyl]zinc (Aldrich; 0.5 M in THF, 2 ml) was added dropwise to a solution of 1-bromo-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D40; 0.15 g) and tetrakis(triphenylphosphine)palladium(0) (50 mg) in THF (5 ml). The resulting solution was heated to reflux for 1 hour. The solvent was evaporated in vacuo and the residue was dissolved in DCM (20 ml). The organic solution was washed with 0.5 M aq. NaOH (8 ml), then dried over anhydrous sodium sulphate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by column chromatography to give the title compound (0.1 g).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:33]3[CH2:38][CH2:37][CH:36]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)[CH2:35][CH2:34]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)[O-])=[C:23]([O:31][CH3:32])[CH:22]=3)[C:13]=12>ClCCl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([C@H:33]3[CH2:38][CH2:37][C@H:36]([N:39]4[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]4)[CH2:35][CH2:34]3)[N:19]=2)=[CH:22][C:23]=1[O:31][CH3:32]
Reactant: COc1cc(-c2nn(C3CCC(N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reaction time: 2 h

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 150 mL) was added to a solution of N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate (4.75 g, 8.85 mmol) in dichloromethane (100 mL) at about 0° C. About 2 hours later, the ice-bath was removed and the solvents were evaporated and the residue was dissolved in dichloromethane. Sodium hydroxide (1.0N) was added to adjust the pH to about 10. The solid formed upon removal of organic solvent was collect by filtration to give trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.85 g, 100%). 1H NMR (DMSO-d6) δ 1.44(m, 2H), 1.96 (m, 6H), 2.21 (s, 3H), 2.33 (m, 5H), 2.53 (m, 4H), 3.83 (s, 3H), 4.60 (m, 1H), 5.03 (bs, 2H), 6.76 (d, J=7.91 Hz, 1H), 6.98 (d, J=7.89 Hz), 7.03 (m, 2H), 8.19 (s, 1H).
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].Cl.[CH3:13]O>C=O>[ClH:1].[CH2:13]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2)[CH2:6][CH2:7][NH:8]1
Reactant: CO
Reactant: NCCc1cccc(O)c1
Agent: C=O
Agent: Cl
Product: Oc1ccc2c(c1)CCNC2
Temperature: 45 °C
Reaction time: 18 h

Procedure:
To a solution of 3-hydroxyphenethylamine hydrochloride (3.0 g) in methanol (6 mL), formaldehyde (37% aqueous solution, 2.7 mL) and a catalytic amount of concentrated hydrochloric acid were added, followed by stirring at 45° C. for 18 hours. The reaction mixture was concentrated and the obtained solid was washed with a mixed solvent of diisopropyl ether-methanol (1:2) to thereby give the title compound (2.8 g) having the following physical properties.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1.F[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]>CN1C(=O)CCC1.O>[N+:23]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:14]=1[NH:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH:7]=1)[C:18]([OH:20])=[O:19])([O-:25])=[O:24]
Reactant: Nc1cccc(-c2nccs2)c1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1ccc(Nc2cccc(-c3nccs3)c2)c([N+](=O)[O-])c1
Yield: 83.4 %

Procedure:
To a solution of 3-thiazol-2-yl-phenylamine (14.0 g, 79 mmol) in anhydrous NMP (50 ml) was added 4-fluoro-3-nitrobenzoic acid (15.0 g, 127 mmol). The resultant mixture was stirred at 90° C. over night. The cooled reaction cake was suspended in water and the solid was filtered off, washed with water and dried in the air to afford the desired product (22.5 g, 83%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:11]([NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][S:9](=[O:38])(=[O:37])[N:8]([CH3:39])[C:7]=2[CH:40]=1.S([O-])(=O)(=O)C.[NH3:46]>>[NH2:46][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:11]([NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:24])=[O:25])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][S:9](=[O:37])(=[O:38])[N:8]([CH3:39])[C:7]=2[CH:40]=1
Reactant: N
Reactant: CN1c2cc(CO)ccc2C(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)CS1(=O)=O
Agent: CS(=O)(=O)[O-]
Product: CN1c2cc(CN)ccc2C(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)CS1(=O)=O

Procedure:
The title compound was prepared from N-(7-hydroxymethyl-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2λ6-benzo[c][1,2]thiazin-4-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Example 12, Step E) via its mesylate and addition of NH3 by a method similar to that described in Example 12, Step E. MS (+ESI, m/z): 579 (M+H)+.
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[N:10]=[C:9]([F:11])[C:8]([F:12])=[C:7](F)[C:6]=1[F:14].[CH2:15]([NH:17][CH2:18]C)C>O>[CH3:15][N:17]([CH3:18])[C:7]1[C:6]([F:14])=[C:5]([F:4])[N:10]=[C:9]([F:11])[C:8]=1[F:12]
Reactant: CCNCC
Reactant: Fc1nc(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: O
Product: CN(C)c1c(F)c(F)nc(F)c1F
Reaction time: 0.5 h

Procedure:
To methylene chloride (50 mL) cooled in an ice bath was added pentafluoropyridine (2.0 g, 11.8 mmol) and diethylamine (2.97 mL of a 40% solution in water, 24 mmol). After stirring for 30 minutes the solution was washed with water, and dried over basic alumina. The solvent was removed in vacuo to give 4-dimethylamino-2,3,5,6-tetra-fluoropyridine; NMR (CDCl3) 3.13 (m,6) ppm.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11](I)=[CH:12][CH:13]=3)[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C2C(=CC([O:28][C@H:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:30]([NH2:32])[CH3:31])=CC=2)C=N1)(C)C>>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([O:28][C@H:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@@H:30]([NH2:32])[CH3:31])=[CH:12][CH:13]=3)[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)n1ncc2cc(O[C@H](c3ccccc3)[C@H](C)N)ccc21
Reactant: Ic1ccc2c(cnn2C2CCCC2)c1
Product: C[C@H](N)[C@H](Oc1ccc2c(cnn2C2CCCC2)c1)c1ccccc1

Procedure:
Prepared from 1-cyclopentyl-5-iodo-1H-indazole (37c, 158 mg, 500 μmol) as described for 30b. Yield 34 mg (20%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:48]([N:43]1[CH2:44][CH2:45][CH:40]([CH2:39][C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:46])[CH2:41][CH2:42]1)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccccc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 48 %

Procedure:
The desired compound was prepared according to the procedure of Example A20 using of N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and benzoyl chloride as starting materials in 48% yield. LCMS for C31H31ClN7O2 (M+H)+: m/z=568.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([CH2:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: CC(C)(C)C(=O)CS(=O)(=O)c1ccccc1Br
Product: CC(C)(C)C(=O)CS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-((2-bromophenyl)sulfonyl)-3,3-dimethylbutan-2-one. MS (ESI): mass calcd. for C22H22FN3O3S, 427.14; m/z found, 428.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 8.51 (d, J=1.5, 2H), 8.09 (dd, J=8.0, 1.3, 1H), 7.82-7.76 (m, 1H), 7.75-7.69 (m, 1H), 7.68-7.62 (m, 1H), 7.44 (dd, J=7.6, 1.3, 1H), 7.39-7.34 (dd, J=11.6, 1.8, 1H), 7.29 (dd, J=7.9, 1.7, 1H), 6.96 (s, 2H), 4.44 (s, 2H), 0.94 (s, 9H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[CH3:40][C:41]1([CH:47]=[O:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>O1CCCC1>[CH3:40][C:41]1([CH:47]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[N:9]=3)[NH:4][CH:3]=2)[OH:48])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: CC1(C=O)CCCCC1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(C(O)C4(C)CCCCC4)c3n2)cc(OC)c1OC
Reaction time: 0.33 h
Yield: 45.3 %

Procedure:
A solution of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (247 mg, 0.435 mmol) in anhydrous tetrahydrofuran (5 ml) was cooled to −78° C. and treated with iPrMgCl—LiCl (1M in tetrahydrofuran, 0.87 ml, 0.87 mmol) dropwise. The reaction mixture was allowed to stir for 20 minutes, and then 1-methyl-cyclohexanecarbaldehyde (219 mg, 1.74 mmol) was added rapidly. The reaction mixture was allowed to stir at −78° C. for 1 hour and then room temperature for 1 hour. The reaction mixture was partitioned between EtOAc/saturated aqueous. NH4Cl. The organic layers were collected, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography using 15-100% EtOAc in hexanes as eluant to provide 81 mg (45%) of (1-methyl-cyclohexyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanol as a pale yellow solid. M+H=412.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])=[CH:5][CH:4]=1)=O.Cl.[OH:18][NH2:19].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:18][N:19]=[CH:1][C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(=O)NCC(F)(F)F)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(NCC(F)(F)F)c1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 89.6 %

Procedure:
In a solution of 4.11 g of 4-formyl-N-(2,2,2-trifluoroethyl) benzoic acid amide in 30 ml of ethanol and 10 ml of water, 1.99 g of hydroxyamine hydrochloride and 2.51 g of anhydrous sodium acetate were added, stirred at room temperature for 3.5 hours. After the completion of the reaction, the reaction mixture was poured in 100 ml of water, and then extracted with ethyl acetate (30 ml×3), the organic phase was washed with 50 ml of saturated sodium hydrogen carbonate aqueous solution, then dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residual solid was washed with hexane to obtain 3.92 g of the aimed product as white crystal.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[N:21]=[N:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[N:21]=[N:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: CCc1ccc(Br)nn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Product: CCc1ccc(-c2cc(C)c(Cl)c(C)c2)nn1

Procedure:
The title compound is prepared from 2-cloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 3-bromo-6-ethyl-pyridazine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 11): tR=1.00 min; Mass spectrum (ESI+): m/z=247/249 (Cl) [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].I[CH2:24][CH3:25]>O>[CH2:24]([N:11]1[N:12]=[N:13][C:9]([CH2:8][C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:10]1)[CH3:25]
Reactant: O=[N+]([O-])c1ccc(Cc2nnn[nH]2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nnc(Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a mixture of 5-(4-nitrobenzyl)-1H-tetrazole (5.0 g) and N,N-dimethylformamide (200 mL) was added sodium hydride (60% in oil, 1.17 g) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. and iodoethane (5.69 g) was added at 0° C. The reaction mixture was stirred at 0° C. for 2 hrs. and water was poured into the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-ethyl-5-(4-nitrobenzyl)-2H-tetrazole as a brown oil (2.70 g, yield 48%) from a fraction eluted with hexane-ethyl acetate (2:1-1:2, v/v).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH2:10]([CH:12]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:13][NH:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]1)[CH3:11].[OH-].[Na+]>CC(C)=O.O>[Cl:3][C:2]1[N:1]=[C:8]([N:14]([CH2:13][CH:12]([CH2:10][CH3:11])[CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:21])([CH3:22])[CH2:20]2)[N:7]=[C:5]([N:14]([CH:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:21])([CH3:22])[CH2:20]2)[CH2:13][CH:12]([CH2:10][CH3:11])[CH2:25][CH2:26][CH2:27][CH3:28])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCC(CC)CNC1CC(C)(C)NC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCC(CC)CN(c1nc(Cl)nc(N(CC(CC)CCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 4 h

Procedure:
A suspension of 9.2 g of cyanuric chloride in 60 ml of acetone and 20 ml of water was added dropwise, with stirring, at 20°-25° C. to a solution of 29.5 g of 4-(2-ethylhexylamino)-2,2,6,6-tetramethylpiperidine in 50 ml of acetone, after which a solution of 4.2 g of sodium hydroxide in 20 ml of water was added to the mixture. The resulting reaction mixture was then stirred for 4 hours at 45°-50° C. At the end of this time, the acetone was distilled off and the oily residue was extracted with ethyl acetate. The extract was dried over anhydrous potassium carbonate, and the ethyl acetate was distilled off. The resulting oil was purified by column chromatography through silica gel, eluted with a 4:1 by volume mixture of hexane and ethyl acetate, to give the title compound as a colourless oil. The Rf value of this compound on thin layer chromatography was 0.62, using silica gel and using, as developing solvent, a 4:1:0.4 by volume mixture of ethyl acetate, methanol and triethylamine.
Reaction SMILES: [CH:1]([C:4]1([CH3:21])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[N:5]1)([CH3:3])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([N:7]1[C:8](=[O:9])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:21])[N:5]=[C:6]1[C:10]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(C)nc1C1=NC(C)(C(C)C)C(=O)N1
Product: COC(=O)c1ccc(C)nc1C1=NC(C)(C(C)C)C(=O)N1C(C)=O

Procedure:
A solution of 33.2 g of methyl 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-6-methylnicotinate in 350 mL of acetic anhydride is stirred and heated at reflux for 4 hours. The solution is concentrated in vacuo, and the residue is triturated with 2:1 hexane-ether to give the desired product as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:17][CH:18]=1
Reactant: Clc1ccc(Br)nc1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccc(Cl)cn1
Yield: 80 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-5-chloropyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 118 mg, 80%) which was obtained as a light yellow solid. MS: m/e=297.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[N:23]=[CH:22][S:21][C:19]4=3)[N:14]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:13]2=[O:29])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[C:30]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH2:24]([N:14]1[C:15]2[C:20](=[C:19]3[S:21][CH:22]=[N:23][C:18]3=[CH:17][CH:16]=2)[C:12]2([C:3]3=[CH:4][C:5]4[O:10][CH2:9][CH2:8][O:7][C:6]=4[CH:11]=[C:2]3[O:1][CH2:30]2)[C:13]1=[O:29])[CH2:25][CH:26]([CH3:27])[CH3:28]
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: CC(C)CCN1C(=O)C(c2cc3c(cc2O)OCCO3)c2c1ccc1ncsc21
Product: CC(C)CCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c1ccc1ncsc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 8-(7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-isopentyl-6H-thiazolo[5,4-e]indol-7(8H)-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6′-isopentyl-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,8′-thiazolo[5,4-e]indol]-7′(6′H)-one was obtained (17%) as a colorless solid: mp 169-171° C.; 1H NMR (300 MHz, CDCl3) δ8.89 (s, 1H), 8.18 (d, J=8.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 6.21 (s, 1H), 4.84 (ABq, 2H), 4.30-4.17 (m, 2H), 4.17-4.08 (m, 2H), 4.03-3.89 (m, 1H), 3.90-3.75 (m, 1H), 1.91-1.51 (m, 3H), 1.04 (d, J=6.1 Hz, 6H); MS (ES+) m/z 423.1 (M+1).