Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH:10]1[CH:14]=[CH:13][CH2:12][C:11]1=[O:15])([OH:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCCC/C=C\C1C=CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CCCC/C=C\C1=CCCC1=O

Procedure:
A solution of 3 g. of crude 2-(6-carboxy-2-cis-hexenyl)cyclopent-3-en-1-one (Example 56) in 100 ml. of aqueous sodium carbonate (pH: 10-11) is stirred at ambient temperature under nitrogen for 4 hours. The solution is acidified to Congo Red and extracted into ether. The ethereal extracts are dried over sodium sulfate and evaporated at reduced pressure to afford the product. See also P. A. Grieco and J. J. Reap, J. Org. Chem., 38, 3413 (1973).
Reaction SMILES: [I-].[Cl:2][C:3]1[C:4]([CH2+:17]2N(C)C(C)(C)C[O:18]2)=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.[BH4-].[Na+]>C(O)C.Cl.O>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[C:4]=1[CH:17]=[O:18]
Reactant: CN1[CH2+](c2c(Cl)cc(Cl)cc2-c2ccc(F)cc2)OCC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [I-]
Solvent: O
Solvent: CCO
Product: O=Cc1c(Cl)cc(Cl)cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A vigorously stirred suspension of 2-(3,5-dichloro-4'-fluoro-2-[1,1'-biphenyl]yl)-3,4,4-trimethyl-2-oxazolium iodide (5.9 g, 12.3 mmol) in ethanol (50 ml) was treated portionwise with sodium borohydride (550 mg, 18 mmol). After stirring for two hours at ambient temperature the clear solution was diluted with 3N hydrochloric acid (100 ml) and stirred on a steam bath for two hours. The reaction mixture was then cooled, diluted with H2O (200 ml) and extracted with ether (300 ml). The ether extract was washed with H2O (2×200 ml) and brine, then dried (MgSO4), filtered and evaporated in vacuo to provide 2.72 g (82%) of the title compound, mp 66°-68° C. Crystallization from petroleum ether provided an analytical sample of the title compound, mp 73°-74° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([CH3:18])[C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2.[CH:20]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:18][C:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:19])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)([CH3:20])[C:15]([OH:17])=[O:16]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C(=O)O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C)CCC(C)(C)c2cc(C(C)(C)C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2 g of (RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-propanoic acid dissolved in 100 ml THF were treated with 9.6 ml of a 2M lithium diisopropylamide solution, at −23° C. The mixture was kept at that temperature for 15 min. then, 1.19 ml of methyl iodide were added dropwise. The reaction mixture was kept at 0° C. for 4 hours then allowed to warm at room temperature for several days. The mixture was quenched with 100 ml of 1N hydrochloric acid solution. The mixture was extracted with three portions of 100 ml of ethyl acetate. The combined organic extracts were washed with 100 ml of a saturated aqueous sodium chloride solution. The organic phase was dried with MgSO4, and the solvent was evaporated. The yellow oil was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes). 1H NMR (CDCl3): 7.31 (d, J=2.2 Hz, 1H), 7.24 (d, J=8.3 Hz, 1H), 7.15 (dd, J=8.3, 2.2 Hz, 1H), 1.67 (s, 4H), 1.58 (s, 6H), 1.27 (s, 6H), 1.26 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([OH:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2C(=O)O)CC1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Cl)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-Carboxy-4-chloro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.64 g, 1.88 mmol) in toluene: methanol (9:1) was added a trimethylsilyldiazomethane (2.0 M in hexanes) (1.05 mL, 2.07 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and purified using gradient elution from hexane/ethyl acetate (10%) to hexane/ethyl acetate (50%). 1H-NMR (CDCL3) δ: 1.45 (9H, s), 2.90–3.00 (4H, m), 3.50–3.60 (4H, m), 3.90 (3H, s), 6.90–7.00 (1H, d), 7.35–7.45 (1H, dd), 7.80 (1H, d). ESI-MS m/z: 355 (M+1), UV retention time: 3.11 min.
Reaction SMILES: [C:1]([CH2:9][CH:10](OC)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[C:1](/[CH:9]=[CH:10]/[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(CC(=O)c1ccccc1)OC
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A mixture of 268 mg of methyl β-benzoyl-α-methoxypropionate, 150 mg of paratoluenesulfonic acid monohydrate and 5 ml of toluene was stirred at 80° C. for 1 hour. A pressure was reduced with an aspirator and a total amount of the resultant was reduced to 1/2 by concentration. The resultant was stirred at 80° C. for 20 minutes and was left for cooling. The reaction mixture was distributed between ethyl acetate and water and the ethyl acetate layer was washed with a saturated solution of NaHCO3 and then with water, and was dried with anhydrous magnesium sulfate. The solvent was distilled away to give 206 mg of methyl trans-β-benzoylacrylate as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=2)[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]#[N:29]>CN(C=O)C.CCOC(C)=O>[C:28]([CH2:27][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=2)[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:29]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC#N)c2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 4.0 g, 15.3 mmol) in dry DMF (50 mL) is added K2CO3 (6.3 g, 45.9 mmol). The reaction mixture is stirred under N2 for 30 min. Bromoacetonitrile (2.1 mL, 30.6 mmol) is added and the reaction mixture is heated to 80° C. for 4 h. After cooling, the reaction mixture is taken up in EtOAc (300 mL) and washed with water, then brine, dried (Na2SO4) and concentrated. The residue is recrystallized from ethanol to afford the title compound (3.9 g, 84%) as fine off-white needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1I>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[N:17]([C:24]3[CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: FC(F)(F)c1ccc(Cl)c(I)c1
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Product: O=C1N(c2cc(C(F)(F)F)ccc2Cl)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 1-chloro-2-iodo-4-trifluoromethyl-benzene. White solid. MS (ESI): 507.0 MH+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:18]=[CH:17][C:10]([CH2:11][CH:12]([CH2:15][OH:16])[CH2:13][OH:14])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[CH:22](OCC)[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])C>>[CH:1]1([O:6][C:7]2[CH:18]=[CH:17][C:10]([CH2:11][CH:12]3[CH2:13][O:14][CH:22]([CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:16][CH2:15]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(CCCNC(C)=O)OCC
Reactant: OCC(CO)Cc1ccc(OC2CCCC2)cc1
Product: CC(=O)NCCCC1OCC(Cc2ccc(OC3CCCC3)cc2)CO1

Procedure:
2-(4-Cyclopentyloxybenzyl)propane-1,3-diol (92 mg, 337 μmol) was reacted with N-(4,4-diethoxybutyl)acetamide in analogy to example 3d. Yield: 81 mg (60%), M+H+: 362.27.
Reaction SMILES: [C:1]([C:6]([OH:8])=[O:7])#[C:2][C:3](O)=[O:4].[CH2:9]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[S:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO.O1CCCC1>[CH2:24]([N:23]1[C:3](=[O:4])[C:2](=[CH:1][C:6]([OH:8])=[O:7])[S:22][C:21]1=[N:20][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCNC(=S)NCCCCCCCCCCC
Reactant: O=C(O)C#CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.6 %

Procedure:
Acetylenedicarboxylic acid (4.8 g, 40 mmoles) is added to a warm solution of N,N'-diundecylthiourea (15.0 g, 39 mmoles) in methanol (200 mls) and tetrahydrofuran (100 mls). The mixture is stirred for 16 hours at ambient temperature, then concentrated under reduced pressure and cooled. The precipitate is filtered off, rinsed with cold methanol and dried. Recrystallization from methanol afforded the product (15.3 g), mp 67°-68° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:25])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C>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].C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:3](=[O:17])[CH2:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)CC2)cc1
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C2=C(c3cc(F)cc(F)c3)C(=O)CC2)cc1
Reaction time: 0.17 h
Yield: 30.3 %

Procedure:
To a mixture of 2-bromo-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one (664 mg, 2.11 mmol), 3,5-difluorophenylboronic acid (832 mg, 5.27 mmol), tris(dibenzylideneacetone)dipalladium(0) (83 mg, 0.09 mmol), and triphenylphosphine (96 mg, 0.36 mmol) was added 40 mL of 3:1:1 toluene:n-propanol:water and the mixture was purged with nitrogen. After stirring 10 min, diethylamine (1.1 mL, 10.6 mmol) was added and the solution was heated to reflux for 4 h. The mixture was cooled and partitioned between 1M NaOH and EtOAc. The organic phase was washed with water, 1M HCl and brine, and dried over MgSO4. Purification by silica gel chromatography, eluting with 50% CH2Cl2 /hexanes, followed by crystallization from CH2Cl2 /ether/hexanes gave the title compound (223 mg).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][CH:12]([NH:14][CH:15]1[C:20]2=[C:21]([CH3:28])[C:22]3[C:27]([N:19]2[CH2:18][CH2:17][CH2:16]1)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:13]>O1CCCC1>[CH3:28][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]2[CH2:18][CH2:17][CH2:16][CH:15]([N:14]([CH:12]([CH3:13])[CH3:11])[CH:1]=[O:3])[C:20]=12
Reactant: O=CO
Reactant: Cc1c2n(c3ccccc13)CCCC2NC(C)C
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: Cc1c2n(c3ccccc13)CCCC2N(C=O)C(C)C
Temperature: 60 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
A mixture of formic acid (6 mL) and acetic anhydride (12 mL) was heated at 60° C. for 4 hours. A solution of 6,7,8,9-tetrahydro-N-(1-methylethyl)-10-methylpyrido[1,2-a]indol-9-amine (6 g, 24.7 mmol, described in Example 22) in tetrahydrofuran (60 mL) was added at once at 25° C. under exclusion of moisture. The reaction mixture was stirred at 25° C. for 12 hours, then poured into ice water (120 mL). The product was extracted with ether (3×80 mL), and the combined organic layer washed with 5% HCl, 10% NaHCO3, and water. The separated organic layer was dried over MgSO4, filtered, and evaporated to afford 6 g (90%) of the title compound as an amber oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:11][C:12](=[O:21])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([O:8][CH2:9][C@@H:10]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH2:11][C@@H:12]([OH:21])[CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@@H](COCc1ccccc1)OC1CCCCO1
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@@H](COCc1ccccc1)OC1CCCCO1

Procedure:
In 2.0 ml of methanol was dissolved 1.0 g (2.55 mmol) of tert-butyl (S)-6-benzyloxy-3-oxo-5-tetrahydropyranyloxyhexanoate of formula (2) obtained in Reference Example 5 and the enantioselective hydrogenation reaction was carried out as in Example 1 using Ru2Cl4 [(R)-Tol-BINAP]2N(CH2CH3)3 of formula (3) for 18 hours with stirring under a hydrogen pressure of 30 kg/cm2 and at a reaction temperature of from 35° to 40° C. After the reaction was over, the solvent was recovered and the residue formed was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate 85/15 by volume) to provide 350 mg (0.89 mmol, percent yield 35%) of tert-butyl (3R,5S)-6-benzyloxy-3-hydroxy-5-tetahydropyranyloxyhexanoate of formula (1) as a colorless transparent liquid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[C:29]([F:30])=[C:28](F)[C:27]([F:32])=[C:26]([F:33])[C:25]=3[F:34])=[CH:15][CH:14]=2)=[C:7]2[C:3]=1[C:4]([CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:5]([CH3:41])[N:6]2[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].CCCCCCC>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][C:27]([F:32])=[C:26]([F:33])[C:25]=3[F:34])=[CH:15][CH:14]=2)=[C:7]2[C:3]=1[C:4]([CH2:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:5]([CH3:41])[N:6]2[CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]
Reactant: Cc1c(CCCC(=O)O)c2c(F)ccc(C#Cc3ccc(OCCCCc4c(F)c(F)c(F)c(F)c4F)cc3)c2n1CCCC(=O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(CCCC(=O)O)c2c(F)ccc(C#Cc3ccc(OCCCCc4c(F)cc(F)c(F)c4F)cc3)c2n1CCCC(=O)O
Temperature: 0 °C
Yield: 80.2 %

Procedure:
The compound (50 mg) prepared in Example 10 (2) was dissolved in ethyl acetate (1.4 mL) at 70° C. To the solution, n-heptane (0.68 mL) was added at room temperature, which was then cooled to 0° C. The crystal was filtered and dried under reduced pressure to obtain the title compound (39 mg).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]([OH:10])=O.S(Cl)([Cl:13])=O>CN(C)C=O.C1(C)C=CC=CC=1>[ClH:13].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:8]([Cl:1])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: Cc1[nH]cnc1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1[nH]cnc1C(=O)Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a suspension of 880 g (5.4 moles) of 5-methyl-4-imidazolecarboxylic acid hydrochloride in 100 ml of dimethylformamide and 2 liters of toluene at 60° C., there was added slowly over 2 hours 790 ml (10.8 moles) of thionyl chloride. At the end of the addition, the mixture was held with good stirring for 1 hour at 80° C. It was allowed to cool, filtered, the solid was washed with 1 liter of toluene. 685 g of 5-methyl-4-imidazolecarbonyl chloride hydrochloride were obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:22]2[CH:30]=[C:29]3[C:25]([C:26]([NH:39][C:40](=[O:44])[CH2:41][CH2:42][CH3:43])=[N:27][N:28]3[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[CH:24][CH:23]=2)O1>O1CCOCC1.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.O.C(OCC)(=O)C>[N:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH:30]=[C:29]3[C:25]([C:26]([NH:39][C:40](=[O:44])[CH2:41][CH2:42][CH3:43])=[N:27][N:28]3[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:36])[CH3:37])=[CH:24][CH:23]=2)=[CH:3][CH:4]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: Ic1ccncc1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccncc3)ccc12
Yield: 97.9 %

Procedure:
246 mg of 4-iodopyridine, 10 cm3 of water, 201 mg of sodium carbonate and 69 mg of tetrakis(triphenylphosphine)palladium are added to 320 mg of N-[6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 20 cm3 of dioxane. The medium is refluxed for 20 hours, the mixture is then allowed to return to room temperature and 50 cm3 of ethyl acetate and 50 cm3 of water are added. The combined organic phases are washed with 50 cm3 of distilled water and then with 50 cm3 of saturated aqueous sodium chloride solution, and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). 280 mg of N-[6-(4-pyridyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a yellow oil.
Reaction SMILES: [C:1]1([CH3:34])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=3)[C:12]([Sn](CCCC)(CCCC)CCCC)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:35]([O:37][C:38]([C:40]1[CH2:44][CH2:43][CH2:42][C:41]=1OS(C(F)(F)F)(=O)=O)=[O:39])[CH3:36].C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[CH2:35]([O:37][C:38]([C:40]1[CH2:44][CH2:43][CH2:42][C:41]=1[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=2)[N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:34])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH:11]=1)=[O:39])[CH3:36]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(C#N)cc23)CCC1
Temperature: 60 °C
Yield: 73.2 %

Procedure:
1-(Toluene-4-sulfonyl)-3-tributylstannanyl-1H-indole-5-carbonitrile (5.60 g, 9.56 mMol), 2-trifluoromethanesulfonyloxy-cyclopent-1-enecarboxylic acid ethyl ester (2.75 g, 9.56 mMol), triphenyl arsine (0.29 g, 0.96 mMol) and tris(dibenzylidenacetone)dipalladium(0) (0.44 g, 0.48 mMol) were dissolved in DMF and degassed for 5 min with a stream of nitrogen. The reaction was heated under nitrogen at 60° C. for 5 min. The reaction was poured into brine (500 mL) and extracted with ethyl acetate (2×100 mL). The organics were mixed with saturated aqueous potassium fluoride (100 mL) and the resulting solids were removed by filtration through celite. The layers of the filtrate were separated and the organic layer was dried with magnesium sulfate and evaporated in vacuo. The solid product was recrystallized from hot ethyl acetate/hexanes to provide the product as a white solid (3.04 g, 73%). 1H NMR (400 MHz, CDCl3) δ 8.05 (1H, d, J=8.7 Hz), 7.87 (1H, s), 7.79 (2H, d, J=8.5 Hz), 7.71 (1H, d, J=1.2 Hz), 7.53 (1H, dd, J=8.8, 1.5 Hz), 7.27 (2H, m), 4.01 (2H, q, J=6.9 Hz), 2.86 (4H, m), 2.36 (3H, s), 2.03 (2H, pentet, J=7.7 Hz), 0.95 (3H, t, J=7.1 Hz); MS m/e 457.0 (M+Na).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C:17]([C:18](OC)=O)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1(CCN2C(CO)=NC3C2=NC=NC=3N)CCCCC1.P(Br)(Br)[Br:50]>O1CCCC1.C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][N:9]2[C:17]([CH2:18][Br:50])=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: COC(=O)c1nc2c(N)ncnc2n1CCC1CCCCC1
Agent: Nc1ncnc2c1nc(CO)n2CCC1CCCCC1
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Nc1ncnc2c1nc(CBr)n2CCC1CCCCC1

Procedure:
A mixture of N9-cyclohexylethyl-8-bromoadenine (1 mmol), tetrakis (triphenylphosphine)palladium (0.05 mmol), and triethylamine (5 mmol) in DMF in a sealed tube was warmed at 110° C. under 50 psi of carbon monoxide. After 24 h the cooled reaction mixture was evaporated and purified through chromatography to give N9-cyclohexylethyl-8-methoxycarbonyladenine as a yellow solid. Step B. A solution of N9-cyclohexylethyl-8-methoxycarbonyladenine (1 mmol) in tetrahydrofuran was treated with lithium aluminum hydride (1 mmol) at 0° C. for 1 h. Extraction and chromatography give N9-cyclohexylethyl-8-hydroxymethyladernine as a white solid. Step C. A solution of N9-cyclohexylethyl-8-hydroxymethyladenine (1 mmol) in methylene chloride was treated with PBr3 (1 mmol) at 25° C. for 1 h. Extraction and chromatography give N9-cyclohexylethyl-8-bromomethyl-adenine as a white solid. Step D. A solution of N9-cyclohexylethyl-8-bromomethyladenine (1 mmol) in DMF was treated with a solution of diethyl hydroxymethylphosphonate sodium salt (1 mmol) in DMF at 25° C. for 1 h. Extraction and chromatography gave N9-cyclohexylethyl-8-diethylphosphonomethoxy-methyladenine as a white solid. Step E. N9-cyclohexylethyl-8-diethylphosphonomethoxymethyladenine was subjected to Step F in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.[H][H]>C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(/C=C/c2ccccc2C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ncccc1CN1CCC(CCc2ccccc2C)CC1
Yield: 97.7 %

Procedure:
In ethanol (10 ml) was dissolved 473 mg of 1-[(2-methoxy-3-pyridinyl)methyl]-4-[(E)-2-(2-methylphenyl)-1-ethenyl]piperidine. To the mixture was added 100 mg of 10% palladium-carbon powder (water-containing product) was added thereto, followed by stirring at room temperature under normal pressure overnight in a hydrogen atmosphere for 1.5 hours. The reaction solution was filtered, and then the filtrate was evaporated, to give 465 mg of the title compound as a colorless oil.