Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH:25]([CH3:27])[CH3:26])[CH2:5][CH2:6][C:7]([CH2:16][CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:8]#[N:9])([CH3:3])[CH3:2].[OH-:28].[Na+]>S(=O)(=O)(O)O>[CH:22]([N:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][C:7]([CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:25]([CH3:27])[CH3:26])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]([NH2:9])=[O:28])([CH3:24])[CH3:23]
Reactant: [OH-]
Reactant: CC(C)N(CCC(C#N)(CCN(C(C)C)C(C)C)c1ccccc1)C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)N(CCC(CCN(C(C)C)C(C)C)(C(N)=O)c1ccccc1)C(C)C
Temperature: 0 °C

Procedure:
2 Parts of α,α-bis[2-(diisopropylamino)ethyl]-α-phenylacetonitrile is dissolved in 20 parts by volume of concentrated sulfuric acid and the resulting solution heated on a steam bath for about 90 minutes. The solution is then cooled to about 0° C. and made alkaline by the addition of dilute sodium hydroxide. The alkaline solution is extracted with ether, the ether extract dried over calcium sulfate and stripped of solvent to afford α,α-bis[2-(diisopropylamino)ethyl]-α-phenylacetamide, melting at about 102°-103° C. after crystallization from hexane. This compound has the following structural formula ##STR13##
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:29][C:17]2[N:18]=[CH:19][N:20]=[C:21]([O:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]3)[C:16]=2[C:15]=1[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1.[CH3:38][O:39][C:40](=[O:45])[CH2:41][CH2:42][CH2:43]Br.Cl>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O.CN(C=O)C>[CH3:38][O:39][C:40](=[O:45])[CH2:41][CH2:42][CH2:43][N:25]1[CH2:26][CH2:27][CH2:28][C@@H:23]([O:22][C:21]2[C:16]3[C:15]([C:30]4[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)=[C:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[F:7])[O:29][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:24]1
Reactant: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCNC4)c23)cc1
Reactant: COC(=O)CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CCCN1CCC[C@@H](Oc2ncnc3oc(-c4ccccc4F)c(-c4ccc(OC)cc4)c23)C1
Temperature: 80 °C
Reaction time: 13 h

Procedure:
411 mg (3.0 mmol) of potassium carbonate are added to a suspension of 500 mg (1.2 mmol) of 6-(2-fluorophenyl)-5-(4-methoxyphenyl)-4-[(3R)-piperidin-3-yloxy]furo[2,3-d]pyrimidine in 10 ml of THF. Then add 0.18 ml (259 mg, 1.4 mmol) of 4-bromobutyric acid methyl ester and 17 mg (0.05 mmol) of tetra-n-butylammonium iodide. Stir the reaction mixture at 80° C. for 13 hours. Then add 10 ml of DMF and again stir the mixture at 70° C. for 13 hours. After adding 10 ml each of water, 1N hydrochloric acid and ethyl acetate, remove the organic phase, concentrate under reduced pressure and purify the residue by means of preparative RP-HPLC eluent: water/acetonitrile gradient). 146 mg (22% of theory) of the target compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[C:12]([C:14]3[C@H:15]([CH3:28])[C@@H:16]4[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:17]4[C:18]=3[C:19]([O-:21])=[O:20])[S:11][C:10]=12.[Na+:29].Cl.C(O[C:34](=[NH:36])[CH3:35])C>>[C:34]([NH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[C:12]([C:14]3[C@H:15]([CH3:28])[C@@H:16]4[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:17]4[C:18]=3[C:19]([O-:21])=[O:20])[S:11][C:10]=12)(=[NH:36])[CH3:35].[Na+:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(SCCCN)c4s3)[C@H](C)[C@H]12
Reactant: CCOC(C)=N
Agent: Cl
Agent: [Na+]
Product: CC(=N)NCCCSc1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Yield: 27.7 %

Procedure:
The procedure of Example 12 was repeated, except that 29.1 mg of sodium (1S,5R,6S)-2-[7-(3-aminopropyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate and 40 mg of ethylacetimidate hydrochloride were used as the starting compounds. Thus, 8.8 mg of the title compound was prepared.
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C(O)C>[F:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:38][CH:39]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]([NH:42][C:40](=[O:41])[C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)=[S:44])=[CH:28][CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(F)cc1
Agent: O=C(N=C=S)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
4-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (69 mg, yield 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21]([OH:24])[C:22]#[CH:23])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([C:21](=[O:24])[C:22]#[CH:23])=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C#CC(O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: C#CC(=O)c1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
To a cold (0° C.) solution of 1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-ol (5.00 g, 15.0 mmol) in chloroform (400 mL) was added manganese dioxide (130 g, 1.50 mol). The reaction mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to provide 1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-α]pyridin-3-yl]-2-propyn-1-one (3.44 g, 690/%) as a clear oil. Rf 0.39 (4:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.61 (d, 1H), 7.72–7.69 (m, 3H), 7.17 (m, 2H), 3.06 (s, 1H); MS m/333 (M+1).
Reaction SMILES: O[N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([Cl:23])=[CH:16][C:15]=1[O:24][CH3:25].P(OCC)(OCC)OCC.O>CN(C)C=O>[CH3:25][O:24][C:15]1[CH:16]=[C:17]([Cl:23])[C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[C:3]1[NH:2][C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=1
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1-c1nc(C)c(-c2cccnc2)n1O
Agent: CCOP(OCC)OCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)c([N+](=O)[O-])cc1-c1nc(C)c(-c2cccnc2)[nH]1
Reaction time: 1 h
Yield: 82 %

Procedure:
A mixture of 1-hydroxy-2-(2-methoxy-4-chloro-5-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole (9.7 g) and triethyl phosphite (8.9 g) in N,N-dimethylformamide (100 ml) was stirred at 80°-90° C. for one hour. The reaction mixture was poured into water and the resultant mixture was stirred at ambient temperature for one hour. The precipitate was collected by filtration and washed with water and ethyl acetate and dried to give 2-(2-methoxy-4-chloro-5-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole (7.6 g).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][CH3:31])[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](OC3C=CC=CC=3)[C:10]=2[N:24]=1.[OH-].[Na+]>O>[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30][CH3:31])[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH2:5])[C:10]=2[N:24]=1
Reactant: [NH4+]
Reactant: CSCCCCCn1c(C)nc2c(Oc3ccccc3)nc(C)c(C)c21
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSCCCCCn1c(C)nc2c(N)nc(C)c(C)c21
Temperature: 160 °C
Yield: 50 %

Procedure:
Ammonium acetate (25 g) and 2,6,7-trimethyl-1-[5-(methylthio)pentyl]-4-phenoxy-1H-imidazo[4,5-c]pyridine (2.75 g, 7.45 mmol) were combined and heated at 160° C. overnight. The reaction mixture was cooled to 0° C. and then diluted with water (50 mL). The pH was adjusted to >13 with 15% sodium hydroxide and then the mixture was extracted with chloroform (2×100 mL). The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified on deactivated silica gel (triethylamine) eluting with 2% methanol in chloroform and then recrystallized from ethyl acetate/hexanes to provide 1.089 g of 2,6,7-trimethyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]pyridin-4-amine as an off white solid, m.p. 121-122° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]([CH3:15])=[C:7]([C:9](N(OC)C)=[O:10])[O:8][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]([CH3:15])=[C:7]([CH:9]=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: CON(C)C(=O)c1oc2cc(F)ccc2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C=O)oc2cc(F)ccc12
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution (50 mL) of 6-fluoro-N-methoxy-N,3-dimethyl-1-benzofuran-2-carboxamide (3.65 g) synthesized above in tetrahydrofuran was added lithium aluminum hydride (292 mg) at 0° C., and the mixture was stirred for 1 hr. Water (300 μL) was added to quench the reaction, 1N aqueous sodium hydroxide solution (600 μL) was added, and the mixture was stirred at room temperature for 1 hr. The resulting insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (1.88 g, 69%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][CH2:5]I.[F:11][C:12]([F:24])([F:23])[CH2:13][CH2:14][S:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:17])=[O:16].[H-].[Na+].Cl>CS(C)=O>[Cl:8][C:3]([F:7])([C:2]([Cl:1])([F:10])[F:9])[CH2:4][CH2:5][CH:18]([S:15]([CH2:14][CH2:13][C:12]([F:23])([F:24])[F:11])(=[O:17])=[O:16])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: FC(F)(Cl)C(F)(Cl)CCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CCC(F)(Cl)C(F)(F)Cl)S(=O)(=O)CCC(F)(F)F
Reaction time: 72 h
Yield: 22.4 %

Procedure:
To a solution of 5.0 g of 1,2-dichloro-1,1,2-trifluoro-4-iodobutane and 3.8 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 100 ml of dimethyl sulfoxide was added 0.7 g of sodium hydride (60% in oil) at room temperature, and the mixture was stirred at the same temperature for 3 days. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 1.50 g of methyl 5,6-dichloro-5,6,6-trifluoro-2-(3,3,3-trifluoropropylsulfonyl)hexanoate (hereinafter referred to as the present compound (1)).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:10]=3[N:11]=2)[CH2:3][CH2:2]1.[O:20]1[CH2:22][CH:21]1[CH2:23][N:24]1[C:32]2[CH2:31][CH2:30][N:29]([C:33](=[O:35])[CH3:34])[CH2:28][C:27]=2[C:26]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)=[N:25]1>CCO>[OH:20][CH:21]([CH2:22][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:10]=3[N:11]=2)[CH2:3][CH2:2]1)[CH2:23][N:24]1[C:32]2[CH2:31][CH2:30][N:29]([C:33](=[O:35])[CH3:34])[CH2:28][C:27]=2[C:26]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)=[N:25]1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: FC(F)(F)c1ccc2sc(C3CCNCC3)nc2c1
Solvent: CCO
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(c3nc4cc(C(F)(F)F)ccc4s3)CC2)C1
Temperature: 60 °C
Yield: 79.5 %

Procedure:
A solution of 63 mg (0.22 mmol) 2-piperidin-4-yl-5-trifluoromethyl-benzothiazole was dissolved in 4 mL EtOH and treated with 40 mg (0.11 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 57 mg (80%) of a white solid. MS (electrospray): exact mass calculated for C31H31F6N5O2S, 651.21. m/z found, 652.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 8.24 (s, 1H), 7.97 (d, J=8.41 Hz, 1H), 7.78 (d, J=8.41 Hz, 1H), 7.70 (m, 2H), 7.65 (d, J=8.41 Hz, 1H), 7.60 (dd, J=8.41, 1.37 Hz, 1H), 4.88 and 4.76 (A and B of AB quartet, J=15.85 Hz, 1H), 4.66 (br s, 1H), 4.25-4.15 (m, 2H), 4.08-3.99 (m, 1.5H), 3.91-3.83 (m, 0.5H), 3.82-3.68 (m, 1H), 3.16 (tt, J=11.35, 3.52 Hz, 1H), 3.12-3.06 (m, 1H), 3.02-2.97 (m, 1H), 2.9-2.87 (m, 1.4H), 2.87-2.75 (m, 0.6H), 2.55-2.43 (m, 3H), 2.27-2.17 (m, 3H), 2.21 (s, 1.5H), 2.17 (s, 1.5H), 2.04-1.87 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][C:9]([CH3:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:7]2[N:22]=[CH:23][C:24]([C:25]#[N:26])=[C:6]12)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:33]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:58].Cl>C1(C)C=CC=CC=1>[ClH:1].[ClH:58].[CH3:11][C:9]1[CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:43]2[CH2:44][CH2:45][N:40]([CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:41][CH2:42]2)[C:6]2[N:7]([N:22]=[CH:23][C:24]=2[C:25]#[N:26])[C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CCl)C1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC1=C(c2cccc(C(F)(F)F)c2)n2ncc(C#N)c2N(C(=O)CN2CCN(Cc3ccccc3)CC2)C1

Procedure:
A mixture of 3.4 g of 4-(chloroacetyl)4,5-dihydro-6-methyl-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 1.1 g of sodium carbonate, 1.7 g of N-benzylpiperazine and 115 ml of toluene was reacted as described in Example 16, giving the base form of the product which was converted to the dihydrochloride salt by the procedure of Example 97, giving 2.4 g, mg 204°-206° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:26][CH3:27].CN(C=O)C>O1CCOCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:26][CH3:27])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:3]=1
Reactant: Fc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cnc2c(Nc3cccc(F)c3)nc(Cl)nc21

Procedure:
1 g (3.47 mmol) of 2-chloro-6-(3-fluoro-phenyl-amino)-purine, 1.8 g (5.5 mmol) of caesium carbonate and 2.3 ml (27.8 mmol) of iodoethane are stirred in 14 ml of a dioxane/water mixture (4:3) and 12 ml of DMF at RT for 16 h. Thereafter, the reaction mixture is diluted with ethyl acetate and the organic phase is washed with water and dried over sodium sulfate. After removal of the solvent, the residue is chromatographed over silica gel (mobile phase: ethyl acetate/hexane=4:1) and 2-chloro-9-ethyl-6-(3-fluoro-phenyl-amino)-9H-purine is isolated; m.p. 136° C.; FAB-MS: (M+H)+=292; Rf=0.7 (CH2Cl2:methanol=9:1).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([NH2:9])=[C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:4]=1.[CH2:21](OC(O)O)C>>[S:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:7]1[CH:6]=[C:5]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:4]=[C:3]2[NH:2][CH:21]=[N:9][C:8]=12
Reactant: CCOC(=O)Nc1cc(-c2cccs2)c(N)c(N)n1
Reactant: CCOC(O)O
Agent: Cl
Product: CCOC(=O)Nc1cc(-c2cccs2)c2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
Hydrochloric acid (35 wt %, 892 μl) was added to 2,3-diamino-4-(2-thienyl)-6-ethoxycarbonylaminopyridine (1.28 g, 4.61 mmol) and orthoformic acid ethyl ester (24.6 ml), followed by stirring at room temperature for 3 days. This solution was filtered and the product was washed with ether to give 7-(2-thienyl)-5-ethoxycarbonylamino-3H-imidazo[4,5-b]pyridine (1.36 g, yield 91%).
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[OH:17].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[O:17][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N)cc1OCCN1CCCC1
Temperature: 25 °C
Yield: 87 %

Procedure:
A stirred DMF suspension (5 mL) of 2-methoxy-5-nitrophenol (0.5 g, 2.96 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (0.75 g (4.43 mmol) and K2CO3 (1.02 g, 7.4 mmol) was heated at 80° C. for 2 hr. After cooling to RT, the reaction was diluted with 20 mL of H2O and extracted with EtOAc (3×20 mL). The combined EtOAc layers were washed brine and dried over MgSO4. After concentration under vacuum, the resulting residue was chromatographed on silica gel. Gradient elution CH2Cl2 to 10% MeOH/CH2Cl2 eluted N-(2-(2-methoxy-5-nitrophenoxy)ethyl)pyrrolidine (507 mg) as a light orange solid. Subsequent conversion of the aryl nitro substituent to the title aryl amine was accomplished in 87% yield following the procedure described in step C of Example 6. MS (ESI) 237 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32]/[CH:33]=[CH:34]/[C:35]2[CH:40]=[CH:39][C:38]([C:41](=[O:53])[N:42]([CH:44]([C:49]([NH:51][CH3:52])=[O:50])[C:45]([O:47][CH3:48])=[O:46])[CH3:43])=[CH:37][CH:36]=2)=[CH:27][CH:26]=1)=O>C(Cl)(Cl)Cl.O>[CH:1]1([NH:4][CH2:23][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[C:32]/[CH:33]=[CH:34]/[C:35]3[CH:40]=[CH:39][C:38]([C:41](=[O:53])[N:42]([CH:44]([C:49]([NH:51][CH3:52])=[O:50])[C:45]([O:47][CH3:48])=[O:46])[CH3:43])=[CH:37][CH:36]=3)=[CH:27][CH:26]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(/C=C/C#Cc2ccc(C=O)cc2)cc1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(/C=C/C#Cc2ccc(CNC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
Cyclopropylamine (99 μL), acetic acid (27 μL) and sodium triacetoxyborohydride (0.10 g) were added to a chloroform (4.0 mL) suspension of 1-formyl-4-[(3E)-4-(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)but-3-en-1-yn-1-yl]benzene (0.20 g) as obtained in Example 22-(3), and the mixture was stirred for 1 hour and 15 minutes at room temperature. Sodium triacetoxyborohydride (0.10 g) was added, and the mixture was stirred for 1.5 hours at room temperature. Water and chloroform were added, and the organic layer was isolated. The extract was dried over anhydrous sodium sulfate, and the desiccant was filtered out. The solvent was distilled off under reduced pressure to obtain 1-[(cyclopropylamino)methyl]-4-[(3E)-4-(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)but-3-en-1-yn-1-yl]benzene (orange oil) (0.20 g, 91%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22](F)[N:21]=2)=[CH:15][CH:14]=1>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[N:4]3)[N:21]=2)=[CH:15][CH:14]=1
Reactant: Fc1cccc(Nc2ccc(Cl)cc2)n1
Reactant: c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(Nc2cccc(-n3ncc4ccccc43)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
Sodium hydride (325 mg, 8.12 mmol) was added to a solution of indazole (800 mg, 6.77 mmol) in N,N-dimethylformamide (10 mL) and stirred for 30 minutes. (4-Chloro-phenyl)-(6-fluoro-pyridin-2-yl)-amine (1.55 g, 6.77 mmol) was added and the reaction mixture was stirred at 80° C. overnight. The mixture was poured into a stirred ice-water solution and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtrated and concentrated in vacuo. The crude product was purified by column chromatography with ethyl acetate-heptane as eluent to give (4-chloro-phenyl)-(6-indazol-1-yl-pyridin-2-yl)-amine (230 mg, 11%) as an yellow solid. LC-ESI-HRMS of [M+H]+ shows 321.0901 Da. Calc. 321.090699 Da, dev. −1.9 ppm
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:6][C@H:7]([CH3:9])[NH2:8].CO[C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1OC)[CH2:20][C@@H:21](C)N.O>C1C=CC=CC=1>[C:19]1([CH:20]([NH:8][CH:7]([CH2:6][C:5]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:9])[CH3:21])[CH:24]=[CH:25][CH:26]=[CH:17][CH:18]=1
Reactant: COc1ccc(C[C@H](C)N)cc1OC
Reactant: COc1ccc(C[C@@H](C)N)cc1OC
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(CC(C)NC(C)c2ccccc2)cc1OC

Procedure:
Said synthesis was developed by D. E. Nichols et al. ("J. Med. Chem.", 1973, 16, 480-48 and U.S. Pat. No. 4,000,197, of 12.28.1976) and was applied to the chiral synthesis of several methoxylated amphetamines, including (S)-3,4-dimethoxy-amphetamine, which is an enantiomer of (3). In U.S. Pat. No. 4,000,197, the synthesis of the iminic intermediate is carried out in benzene under refluxing conditions during 24 hours with formed water being simultaneously azeotroped off; the hydrogenation is carried out with Raney-Nickel as the catalyst, in absolute ethanol under medium-pressure hydrogen (3 atm of H2). The N-α-phenyl-ethyl-3,4-dimethoxy-amphetamine (15) intermediate is isolated as hydrochloride salt, by crystallization in aqueous acetone or acetone/isopropanol blend, in moderate yield (relatively to dimethoxy-phenyl-acetone), of 48%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](=O)[CH2:14]Br)=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+].C(O)C>O>[Br:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]2[N:1]=[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:14]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Brc1ccc(-c2cn3ccccc3n2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 76.6 %

Procedure:
1.0 g (11 mmol) of 2-aminopyridine, 3.0 g (11 mmol) of 4-bromophenacyl bromide, and 1.9 g (14 mmol) of sodium hydrogen carbonate were put in a 50 mL three-neck flask, and the air in the flask was replaced with nitrogen. This mixture was added with 10 mL of ethanol, and then heated and stirred at 80° C. for six hours. After the stirring, the mixture was added with water and subjected to suction filtration to give a solid. The obtained solid was washed with water and methanol in this order, whereby 2.3 g of the target white solid was obtained in a yield of 76%.