Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH:14]=2)[NH2:13])[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:14]=[C:12]([NH2:13])[C:11]([NH2:15])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CC1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC1CCN(c2ccc(N)c(N)c2)CC1
Yield: 86 %

Procedure:
5-(4-Methylpiperidin-1-yl)-2-nitroaniline (200 mg, 0.850 mmol) was added to 10% Pd/C (10 mg) in ethanol (25 mL) and then hydrogen gas (60 psi) was applied for 24 h at room temperature. Upon TLC-based completion of the reaction, the reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (150 mg) as a brown solid. 1H NMR: (400 MHz, DMSO-d6): δ 6.35 (d, 1H, J=8.4 Hz), 6.19 (d, 1H, J=2.4 Hz), 5.99 (m, 1H), 4.29 (bs, 2H), 3.92 (bs, 2H), 3.26 (m, 2H), 2.39 (m, 2H), 1.61 (m, 2H), 1.36 (m, 1H), 1.20 (m, 2H), 0.89 (d, 3H, J=6.8 Hz); ESI-MS [M+H]+: 206.1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]([CH:11]1[CH2:13][CH:12]1[CH2:14][C:15]#[C:16][CH2:17][OH:18])=[O:10].C(N(CC)CC)C.O>ClCCl>[CH3:7][O:8][C:9]([CH:11]1[CH2:13][CH:12]1[CH2:14][C:15]#[C:16][CH:17]=[O:18])=[O:10]
Reactant: COC(=O)C1CC1CC#CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CC1CC#CC=O
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
Oxalyl chloride (0.78 g, 6.2 mmol) was dissolved in dichloromethane (12 ml), and the solution was cooled to -40° C. A solution of dimethylsufloxide (1.0 g, 12.3 mmol) in dichloromethane (4 ml) was dropwise added thereto over a period of 10 minutes. Fifteen minutes later, a solution of 2-(4-hydroxy-2-butynyl)cyclopropanecarboxylic acid methyl ester (0.70 g, 4.1 mmol) in dichloromethane (5 ml) was dropwise added thereto over a period of 15 minutes. Forty minutes later, triethylamine (2.5 g, 25 mmol) was added thereto, and the temperature was raised to 0° C. Water was added thereto, and the product was extracted with dichloromethane, and the crude product thereby obtained was roughly separated by silica gel column chromatography to obtain 2-(4-oxo-2-butynyl)cyclopropanecarboxylic acid methyl ester (0.32 g).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:15]=[O:16].C(C1C=CC2C3C(=CC=CC=3)C=CC=2C=1)(=[O:19])C.C(C1C=CC2C=CC3C(C=2C=1)=CC=CC=3)(=O)C>>[CH:4]1[C:5]2[CH:6]=[CH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:1]=[C:2]([C:15]([OH:16])=[O:19])[CH:3]=1
Reactant: CC(=O)c1ccc2c(ccc3ccccc32)c1
Reactant: O=Cc1ccc2c(ccc3ccccc32)c1
Agent: CC(=O)c1ccc2ccc3ccccc3c2c1
Product: O=C(O)c1ccc2ccc3ccccc3c2c1
Yield: 51 %

Procedure:
Using the procedure outlined in 2A for 2-acetylphenanthrene, 3-acetylphenanthrene (Aldrich, technical grade), 25 g, 0.114 mol) gave 13 g (51%) of phenanthrene-3-carboxylic acid. 15.6 g (0.07 mol) of this acid was converted to the corresponding acid chloride, then to 8.37 g (58%) of phenanthrene-3-carboxaldehyde mp 78°-80° (lit. 79.5°-80°, E. Mosettig and J. van de Kamp, J. Amer. Chem. Soc. 55 2395 (1933)), (C, H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]#[N:11].[NH2:12][C:13]1[CH:19]=[C:18]([Cl:20])[C:17]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:16][C:14]=1N.[Cl-].[NH4+]>Cl>[Cl:20][C:18]1[C:17]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:16][C:14]2[NH:11][C:10]([CH2:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])=[N:12][C:13]=2[CH:19]=1
Reactant: Cc1ccccc1CCC#N
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1ccccc1CCc1nc2cc(Cl)c(S(N)(=O)=O)cc2[nH]1

Procedure:
To 11.5 g of 3-(2-methylphenyl)propionitrile in 50 ml of 6 N hydrochloric acid was added 11.8 g of 2-amino-4-chloro-5 sulfamylaniline and the suspension refluxed for 12 hours. The precipitate was collected by filtration and added with stirring to 200 ml of concentrated ammonium hydroxide. The free base was then collected and added to methanol; the methanol was brought to a boil, charcoal added, and the suspension filtered. Concentration in vacuo provided a semi-solid which upon treatment with acetonitrile gave a red solution and a precipitate (ammonium chloride). Concentration of the red solution in vacuo provided a solid which upon recrystallization from acetonitrile yielded off-white crystals, m.p. 205°-208°.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[S:22]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)[CH2:28][CH2:29]2)=[O:21])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: c1cc(N2CCNCC2)cs1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccsc3)CC2)c(OC)nc1C
Yield: 63 %

Procedure:
Phenyl N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-thiophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][C@@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH3:20])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:27][CH3:28])=[C:5]([CH3:29])[O:4][N:3]=1.[O:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=O)[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:27][CH3:28])=[CH:9][C:10]3[C:11]4[N:18]([CH:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH3:20])[C:36]([CH:33]5[CH2:34][CH2:35][O:30][CH2:31][CH2:32]5)=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: O=C(O)C1CCOCC1
Reactant: COc1cc2c(N[C@H](C)c3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(C3CCOCC3)n(C(C)c3ccccn3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-N4-[(1R)-1-(2-pyridinyl)ethyl]-3,4-quinolinediamine (for a preparation see Intermediate 64, 380 mg) in DCM (20 ml) was added tetrahydro-2H-pyran-4-carboxylic acid (240 mg) followed by HATU (1.2 equiv) and triethylamine (1.5 equiv). The reaction mixture was stirred at room temperature for 1 h, and then hydrolysed using a saturated solution of sodium hydrogen carbonate. The mixture was extracted with DCM and the organic was dried over Na2SO4, filtered and concentrated to dryness. The resulting crude product was diluted in acetic acid (5 ml) and heated at 100° C. overnight. The reaction mixture was then taken-up in a 1:1 mixture of sodium hydroxide (1N) and water (total 100 ml), extracted with DCM and the resulting crude product was purified by chromatography on silica gel eluting with DCM/methanol (95:5). The resulting product was taken-up in diethyl ether and dried under vacuum to give racemic 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[1-(2-pyridinyl)ethyl]-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinoline (400 mg) as a grey powder.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@H:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([F:27])[F:26])=[CH:21][CH:20]=1>C1COCC1>[Si:3]([O:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([F:27])[F:26])=[CH:21][CH:20]=2)[C:12]1=[O:16])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Reactant: FC(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(Cc2ccc(C(F)F)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (232 mg, 5.31 mmol) was added to a stirred solution of (S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (762 mg, 3.54 mmol, intermediate G) in THF (7 mL) at 0° C. After 15 min, a solution of 1-(bromomethyl)-4-(difluoromethyl)benzene (980 mg, 4.43 mmol) in THF (7 mL) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 6 h. The reaction was carefully quenched with several grams of ice pellets. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude reaction mixture was purified using silica gel column chromatography (0-30% EtOAc/hexanes) to afford the desired product (440 mg, 35% yield) as a white solid: LCMS (M+H)+ 356.3; 1H NMR (500 MHz, chloroform-d) δ 7.49 (d, J=8.1 Hz, 2H), 7.35 (d, J=7.9 Hz, 2H), 6.65 (br. t, J=1.0 Hz, 1H), 4.56-4.44 (m, 2H), 4.38 (t, J=7.5 Hz, 1H), 3.27 (ddd, J=9.7, 8.7, 3.4 Hz, 1H), 3.13 (dt, J=9.7, 7.4 Hz, 1H), 2.36-2.27 (m, 1H), 1.98-1.90 (m, 1H), 0.96 (br. s., 9H), 0.22-0.20 (m, 3H), 0.20-0.18 (m, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=1.B(Br)(Br)Br.[B].O>C(Cl)Cl>[OH:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=1
Reactant: COc1ccc2c3ccccc3c3ccccc3c2c1
Agent: BrB(Br)Br
Agent: [B]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc2c3ccccc3c3ccccc3c2c1
Temperature: -78 °C
Reaction time: 5 h
Yield: 95.1 %

Procedure:
Under an argon atmosphere, 13.9 g of 2-methoxytriphenylene was placed in a flask, and 300 mL of methylene chloride was added. The reaction solution was cooled to −78° C., and 54 mL of a solution of 1M boron boron tribromide in methylene chloride was dropwise added thereto. The reaction solution was stirred for 5 hours while increasing temperature of the reaction solution to room temperature. 100 mL of water was added to the reaction solution, followed by filtration. The resulting solid was washed with water and methanol to obtain 12.5 g (yield: 95%) of 2-hydroxytriphenylene.
Reaction SMILES: [C:1]1([CH:11]=[C:12]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:13]([OH:15])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>C(OC(=O)C)(=O)C>[C:1]1([CH:11]=[C:12]2[CH2:16][CH2:17][C:18](=[O:19])[O:20][C:13]2=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCC(=Cc1cccc2ccccc12)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCC(=Cc2cccc3ccccc23)C(=O)O1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of 10 g (37 mmole) of the 2-(1-naphthylmethylene)glutaric acid prepared as described above and 100 ml of acetic anhydride was stirred at 60° C. for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was triturated with a 1: 1 by volume mixture of benzene and hexane to precipitate crystals, which were collected by filtration to give 8.1 g of 2-(1-naphthylmethylene)glutaric anhydride.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([OH:19])=[O:18].O>CN(C)C=O>[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([O:19][CH3:5])=[O:18]
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(N)cc(OC)cc1OC
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Dimethyl sulfate (1.04 ml, 11.0 mmol) was added dropwise to a mixture of potassium carbonate (3.34 g, 24.2 mmol) and 2-amino-4,6-dimethoxybenzoic acid (2.56 g, 11.0 mmol) in dimethylformamide (70 ml) at 0° C. The reaction was stirred for 1 hour, then poured into water. The resulting precipitate was filtered, washed with water and dried in vacuo. The filtrate was extracted with ethyl acetate, and the combined organic extracts were dried (magnesium sulphate) and concentrated in vacuo. The combined solids were dried in vacuo to yield methyl 2-amino-4,6-dimethoxybenzoate (1.8 g, 77% yield) as a yellow crystalline solid:
Reaction SMILES: N1C2C(=CC=C(C(C3C=CC=CC=3)CCN)C=2)C=C1.[CH3:20][O:21][C:22](=[O:42])[NH:23][CH2:24][CH2:25][CH:26]([C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH:35]=[CH:36][NH:37]2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:20][O:21][C:22](=[O:42])[NH:23][CH2:24][CH2:25][CH:26]([C:33]1[CH:34]=[C:38]2[C:39]([CH:35]=[CH:36][NH:37]2)=[CH:40][CH:41]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)NCCC(c1ccccc1)c1cccc2[nH]ccc12
Agent: NCCC(c1ccccc1)c1ccc2cc[nH]c2c1
Product: COC(=O)NCCC(c1ccccc1)c1ccc2cc[nH]c2c1
Yield: 89 %

Procedure:
[3-(1H-Indol-6-yl)-3-phenyl-propyl]-carbamic acid methylester XV (0.554 g, 89% yield) was prepared from 3-(1H-indol-6-yl)-3-phenyl-propylamine using the procedure described for [3-(1H-indol-4-yl)-3-phenyl-propyl]-carbamic acid methylester V (see Example 1).
Reaction SMILES: [C:1]([O:5][CH3:6])(=O)[CH:2]=[CH2:3].[NH2:7][C:8]1[NH:9][C:10]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19]C)=[CH:13][C:11]=2[N:12]=1>CO>[CH3:6][O:5][C:1]1[C:15]([O:17][CH3:18])=[CH:16][C:10]2[N:9]=[C:8]3[NH:7][C:14](=[O:19])[CH2:13][CH2:11][N:12]3[C:3]=2[CH:2]=1
Reactant: C=CC(=O)OC
Reactant: COc1cc2nc(N)[nH]c2cc1OC
Solvent: CO
Product: COc1cc2nc3n(c2cc1OC)CCC(=O)N3
Reaction time: 90 h
Yield: 66 %

Procedure:
Methyl acrylate (6.1 g.) was added to a solution of 2-amino-5,6-dimethoxybenzimidazole (12.2 g.) in methanol (70 ml.) and the mixture was stirred for 90 hours. The crystalline precipitate was separated by filtration and washed with ethanol and then ether to give 7,8-dimethoxy-3,4-dihydropyrimido[1,2-a]-benzimidazol-2(1H)-one (10.3 g.), m.p. 264°-5° C.; microanalysis, C12H13N3O3 requires: C, 58.3; H, 5.3; N, 17.0%; found: C, 58.0; H, 5.2; N, 16.8%; NMR: δ2.82 (t, 2 protons, C3-H2); 3.72 (s, 3 protons, CH3O); 3.76 (s, 3 protons, CH3O); 4.15 (t, protons C4 -H2); 7.00 (s, 1 proton, C6-H); 7.04 (s, 1 proton, C9-H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:19])[C:17]=2[CH3:18])=[CH:8][N:9]=1)[CH:5]=O.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:19])[C:17]=2[CH3:18])=[CH:8][N:9]=1)[CH:5]=[N:21][OH:22]
Reactant: NO
Reactant: Cc1c(F)cncc1C#Cc1cnc(Cl)cc1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(F)cncc1C#Cc1cnc(Cl)cc1C=NO
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-chloro-5-((5-fluoro-4-methylpyridin-3-yl)ethynyl)isonicotinaldehyde (385 mg, 1.4 mmol), hydroxylamine hydrochloride (107 mg, 1.54 mmol), and sodium acetate (138 mg, 1.68 mmol) in ethanol (5 mL) was stirred at 40° C. for 30 minutes. The reaction mixture was then evaporated in vacuo, re-dissolved in DCM and methanol and washed with water (15 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a pale yellow solid that was used in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH:24]=1>>[CH3:18][C:4]1[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:12][CH:13]=2)[CH:7]=[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([N:23]3[CH:24]=[C:20]([CH3:19])[N:21]=[CH:22]3)[CH:26]=2)[N:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Reactant: Cc1cn(-c2cccc(B3OC(C)(C)C(C)(C)O3)c2)cn1
Product: Cc1cn(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)c2)cn1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.31) (400 mg, 1.09 mmol) and 4-methyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole [in situ prepared by the following sequence:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12]([C:14]#[C:15][CH2:16][NH:17]C(=O)C(F)(F)F)[C:10]([NH2:11])=[N:9][C:7]1=[O:8].[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-]>>[OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12]([C:14]#[C:15][CH2:16][NH2:17])[C:10]([NH2:11])=[N:9][C:7]1=[O:8]
Reactant: Nc1nc(=O)n(COCCO)cc1C#CCNC(=O)C(F)(F)F
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Product: NCC#Cc1cn(COCCO)c(=O)nc1N

Procedure:
The hydroxyl group of the sugar part of alkynylamino nucleoside 69 (0.167 mmol) was converted to a triphosphate and the trifluoroacetyl group was removed following the general procedure given in Example 1E. After addition of the second aliquot of phosphorus oxychloride, phosphorylation was allowed to proceed for for 75 min. Assuming an absorption coefficient for the product equal to that of the starting material (7,790), the yield of triphosphate 67, based on its UV absorption at 291 nm, was 21%.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]>ClCCl.[O-2].[Mn+2]>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OCc1ccccc1I
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccccc1I
Temperature: 25 °C
Yield: 90.8 %

Procedure:
In a flask, 2-iodobenzyl alcohol (4 g, 17.09 mmol) was dissolved in dichloromethane (MC, 85 ml), and then, manganese oxide (MnO2, 14.86 g, 170.92 mmol) was added thereto. The obtained reaction product was stirred under the reflux condition. When the reaction was completed, the obtained reaction product was cooled to the room temperature, and then, fiteated and concentrated using celite, to obtain the title compound (3.6 g, yield 91%).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([N:15]=C(C3C=CC=CC=3)C3C=CC=CC=3)[CH:10]=2)[CH2:3]1.Cl>O1CCCC1.O>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)[CH2:3]1
Reactant: C[C@@H]1CN(c2ccnc(N=C(c3ccccc3)c3ccccc3)c2)C[C@H](C)N1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccnc(N)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-[cis-3,5-dimethyl-1-piperazinyl]-N-(diphenylmethylidene)-2-pyridinamine (D20) (650 mg, 1.76 mmol) in tetrahydrofuran (5 ml) was treated with 1.0M hydrochloric acid (5 ml) and the mixture stirred at room temperature for 1 hour. The mixture was diluted with water and washed with diethyl ether. The aqueous phase was basified with 50% aq. sodium hydroxide then saturated with sodium chloride. The mixture was extracted with ethyl acetate (×2). The combined extracts were dried and evaporated to give the title compound (D21). 1H NMR CDCl3 ppm δ (6H, d), 2.33-0.238 (2H, m), 2.91-2.96 (2H, m), 3.58-3.62 (2H, m), 5.85 (1H, s), 6.18-6.20 (1H, m), 7.78-8.00 (1H, d).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH3:21])=O)(C)(C)C.Cl>CO>[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][C@@H:9]([CH3:21])[CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@H]1CN(Cc2ccccc2)CCN1
Temperature: 50 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
To a stirred solution of (S)-1-tert-butoxycarbonyl-2-methyl-4-benzylpiperazine (864 mg) in methanol (5 ml) was added concentrated hydrochloric acid (0.94 ml). The reaction mixture was stirred at 50° C. for 1 hour. After cooling, the solvent was evaporated off. The residue was made to alkali with 1N aqueous solution of sodium hydroxide and extracted with ethyl acetate (×3). The combined organic layer was dried over magnesium sulfate and concentrated to give (S)-1-benzyl-3-methylpiperazine (588 mg).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:14])[CH:13]=[C:8]2[CH:7]=[CH:6]1)(C)C.[CH2:21](N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(OC(=O)N)(C)(C)C.[H-].[Na+].CI>ClCCl.CN(C=O)C>[CH3:21][NH:14][C:12]1[CH:13]=[C:8]2[CH:7]=[CH:6][NH:5][C:9]2=[N:10][CH:11]=1
Reactant: CCN(CC)CC
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(N)cnc21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(N)=O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CI
Product: CNc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 16.2 %

Procedure:
1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (375 mg, 1.3 mmol) and triethylamine (271 μL, 1.95 mmol) in dichloromethane (10 mL) was treated with di-tert-butyl dicarbonate (340 mg, 1.5 mmol) and the mixture was stirred at RT for 2.5 h., quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4.), filtered and concentrated. The residue was purified by preparative HPLC. B. 1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-carbamic acid tert-butyl ester (250 mg, 0.6 mmol) was then treated with sodium hydride (24 mg, 60% oil, 0.6 mmol) and methyl iodide (48 mL, 0.77 mmol) in DMF (2.0 mL). The mixture was stirred at RT for 16 h, quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4.), filtered and concentrated. The residue, which was used with no further purification, was then treated with TFA (1.0 mL) in dichloromethane (4.0 mL) and the mixture was stirred at RT for 10 h, concentrated and purified by preparative HPLC to afford methyl(1H-pyrrolo[2,3-b]pyridin-5-yl)-amine (31 mg, 33%). m/z 148 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][CH:6]([S:8]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:10])=[O:9])[CH2:5]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>C1COCC1.CCCCCC>[CH2:16]([O:3][CH:4]1[CH2:7][CH:6]([S:8]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:10])=[O:9])[CH2:5]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CCCCOS(=O)(=O)C1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCOS(=O)(=O)C1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
60% NaH (0.95 g, 2.52 (CH2)2CH3 mmol) was added to a cooled solution of butyl 3-hydroxycyclobutane-1-sulfonate (0.35 g, 1.68 mmol) in dry THF (20 mL) at 0° C. and the resulting reaction mass was stirred at room temperature for 30 minutes. This was followed by the addition of benzyl bromide (0.43 g, 2.52 mmol) and stirred the resulting mixture at room temperature for 2 hours. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was quenched with ice-water and extracted using ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (4% ethyl acetate in hexane) afforded 0.2 g of the product (50% yield).