Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH2:19]C[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[H-].[Na+].CI>C1C=CC=CC=1>[C:1]1([C:7]2[NH:8][C:9]3[CH2:19][C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3c([nH]2)CCc2ccccc2-3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3c([nH]2)Cc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-phenyl-4,5-dihydro-naphtho[1,2-d]imidazole (2.46 g.) dissolved in 10 ml. of dimethylforamide, 0.5 g. of 55% NaH (mineral oil dispersion) and 1.41 g. of methyl iodide are added. After stirring for two hours at room temperature, and for one hour at 60° C., the mixture is poured into ice water. The resulting solid precipitate is dissolved in benzene and chromatographed through a silica gel column and eluted with benzene containing 10% of ethyl ether for separating the two methylated isomers. The first eluted isomer (1.66 g.) melts at 150° C. (from ethanol) while the second (0.79 g.) melts at 141°-3° C. By operating according to the procedure described in Example 1, utilizing as the starting material 2-bromo-1-indanone, 2-phenyl-1,8-dihydro-indeno[1,2-d]imidazole (m.p. 231-2) is obtained which is in turn methylated according to the procedure described above to give 1-methyl-2-phenyl-8H-indeno[1,2-d]-imidazole, 3-methyl-2-phenyl-8-indeno[1,2-d]imidazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[N:6][CH:7]=1.[CH:10](Br)([CH3:12])[CH3:11]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[N:6]([CH:10]([CH3:12])[CH3:11])[CH:7]=1
Reactant: CC(C)Br
Reactant: Cc1cc(Br)cnc1O
Product: Cc1cc(Br)cn(C(C)C)c1=O

Procedure:
Examples 508-511 as described in Table 22 were prepared in three steps. Using conditions similar to those described in WO2005/40151 (Preparation 6), 5-bromo-3-methylpyridin-2-ol was N-alkylated with isopropyl bromide to give 5-bromo-3-methyl-1-propan-2-ylpyridin-2-one which was then reacted with 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane using conditions similar to those described in Example 248, step 2 to give the pinacol ester, 3-methyl-1-propan-2-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one. This pinacol ester was then substituted for the pinacol ester of the example shown under Synthetic Method in Table 22 and reacted in the same way as the example to obtain the title compounds.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[CH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CON(C)[C:20]([C:22]1[N:23]([CH2:33][CH3:34])[N:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)=[O:21]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]#[C:11][C:20]([C:22]1[N:23]([CH2:33][CH3:34])[N:24]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:26]=1)=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCn1nc(-c2ccccc2)cc1C(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1nc(-c2ccccc2)cc1C(=O)C#CCNC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a −10° C. solution of N-t-butoxycarbonyl propargylamine (502 mg, 3.24 mmoles) in THF (5 mL) was added nBuLi (3.7 mL of a 1.6 M solution in hexanes, 5.94 mmoles) dropwise over 10 minutes. The resulting dianion mixture was stirred at −10° C. for 15 minutes, then treated with a THF solution (2 mL) of the above-prepared 2-ethyl-5-phenyl-2H-pyrazole-3-carboxylic acid methoxy-methyl-amide (125 mg, 482 μmoles), allowed to warm to room temperature, and stirred at room temperature for 2 hours. The resulting mixture was cooled to 0° C., quenched with 2 M NaH2PO4, diluted with ethyl acetate, and vigorously stirred for 5 minutes. The phases were separated, the organic phase dried over Na2SO4, filtered, and concentrated in vacuo. The crude title compound was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:6]=2[CH:34]=1.[C:35]1(=[O:46])[O:41][C:39](=[O:40])[CH:38]2[CH2:42][CH2:43][CH2:44][CH2:45][CH:37]2[CH2:36]1>N1C=CC=CC=1>[CH2:10]([C:8]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[C:6]2[CH:34]=[C:2]([NH:1][C:35]([CH2:36][CH:37]3[CH2:45][CH2:44][CH2:43][CH2:42][CH:38]3[C:39]([OH:41])=[O:40])=[O:46])[CH:3]=[CH:4][C:5]=2[N:9]=1)[CH2:11][CH2:12][CH3:13]
Reactant: O=C1CC2CCCCC2C(=O)O1
Reactant: CCCCc1nc2ccc(N)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: c1ccncc1
Product: CCCCc1nc2ccc(NC(=O)CC3CCCCC3C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 3 h

Procedure:
1.3 g (2.86 mMol) of tert.-butyl 4'-[(6-amino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate, 0.6 g (5.35 mMol) of hexahydrohomophthalic acid anhydride and 5 ml of pyridine are refluxed with stirring for 3 hours. Then the pyridine is removed by rotary evaporation in vacuo, the residue is crystallised from acetone, washed with acetone and dried in vacuo at 70° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>CN(C=O)C>[CH2:34]([O:33][C:31]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[C:15]3[N:16]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[S:9][C:10]=3[N:11]=[C:12]([NH2:23])[N:13]=2)[CH2:22][CH2:21]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Nc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.15 mmol) and pyridine (18 μl, 0.23 mmol) in DMF (1 ml) was added benzyl chloroformate (24 μl, 0.17 mmol). The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was quenched with water, extracted with EtOAc, brine and dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (54 mg, 77%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[BH4-].[Na+]>C(O)C>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(CN[C@H](CO)Cc2ccccc2)cc1
Yield: 87.8 %

Procedure:
A solution of L-phenylalaninol (6.0 g) and 4-methylbenzaldehyde (5.3 g) in ethanol (40 ml) was stirred for 30 minutes at room temperature. Sodium borohydride (2.0 g) was added in small portions with stirring and ice-cooling, and then the mixture was stirred for 1.5 hours at room temperature. After removal of the ethanol by evaporation, the residue was acidified with dilute hydrochloric acid and then made alkaline with aqueous sodium hydroxide. The resulting mixture was extracted with chloroform. The extract was dried over sodium sulfate and the solvent was evaporated. The residue was recrystallized from ethanol to give N-(4-methylbenzyl)-L-phenylalaninol (8.9 g), mp 125°-127° C., [α]D -6.7°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]([NH2:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[S:13](Cl)(Cl)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2=[N:11][S:13][N:12]=[C:4]2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc2nsnc2cc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A solution obtained by dissolving 4-chloro-5-nitrobenzene-1,2-diamine (1) (15 g, 0.0799 mol) in 500 mL of dichloromethane (DCM) is cooled down to 0° C., and thionyl chloride (SOCl2, 11.7 mL, 0.159 mol, 2.0 eq) is slowly dripped into the solution. The reactant is agitated and reflowed for 16 hours, cooled down to room temperature, and condensed under a reduced pressure. The condensate is dissolved again in dichloromethane, cleaned with a saturated NaHCO3 aqueous solution, and subfractionated. An organic layer is dried, condensed under a reduced pressure, and passed through a silica column so as to obtain thin brown solid-phase compound (2) (15 g, yield: 87%). 1H NMR (400 MHz, CDCl3): δ ppm 8.49 (s, 1H), 8.26 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([Br:20])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.ClCCl.N1C=CC=CC=1.[CH2:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH3:33]>O>[Br:20][C:17]1[CH:18]=[C:19]2[C:11]([C:9]([C:4]3[C:3]([F:21])=[C:2]([NH:1][S:34]([CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])[CH:7]=[CH:6][C:5]=3[F:8])=[O:10])=[CH:12][NH:13][C:14]2=[N:15][CH:16]=1
Reactant: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
Into a reaction flask under nitrogen, (3-amino-2,6-difluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (7, 13.00 g, 36.9 mmol) is combined with 150 mL of dichloromethane and anhydrous pyridine (5.84 g, 73.8 mmol), and propane-1-sulfonyl chloride (8, 6.05 g, 42.5 mmol) is added. The reaction is stirred at room temperature overnight, and additional pyridine (1.46 g, 18.5 mmol) and propane-1-sulfonyl chloride (1.51 g, 10.6 mmol) are added. The reaction is stirred at room temperature another 3 hours, then diluted with 500 mL of water and extracted 3×250 mL with dichloromethane. The organic layers are combined and washed with 250 mL of brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of ethyl acetate:hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (9, 8.41 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C(OO)(=[O:11])C.OO.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[N+:6]([O-:11])[C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cn1
Reactant: CC(=O)OO
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(F)c[n+]1[O-]
Temperature: 50 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
To the solution of 5-fluoro-2-picoline obtained in Step 4, at 0° C., was added, with vigorous stirring, a cold solution of 40% peracetic acid (prepared by carefully adding 50 mL of 30% hydrogen peroxide solution to 150 mL of glacial acetic acid). The reaction mixture was heated at reflux temperature (50° C.) for 4 days and then poured into 600mL of ice water. The aqueous mixture was adjusted to pH 9 by the addition of potassium carbonate and then was stirred at ambient temperature for 4 hours. The aqueous solution was continuously extracted with methylene chloride for 24 hours and the methylene chloride extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 30.8 g (22% yield) of the title compound; MS DCI-NH3M/Z: 128 (M+H)+ base; 1H NMR (CDCl3) d 2.48 (s, 3H), 7.00 (ddd, 1H), 7.22 (dd, 1H), 8.22 (dd, 1H).
Reaction SMILES: CO[C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(OC([N:25]1[CH2:29][C@H:28]([CH3:30])OS1(=O)=O)=O)(C)(C)C>>[CH2:10]([O:9][C:7]([N:6]1[CH2:5][CH2:4][C:3](=[O:17])[NH:25][CH2:29][C@H:28]1[CH3:30])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: COC(=O)CCNC(=O)OCc1ccccc1
Product: C[C@@H]1CNC(=O)CCN1C(=O)OCc1ccccc1

Procedure:
In analogy to the procedure described in intermediate 78A, 3-benzyloxycarbonylamino-propanoic acid methyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (Bioorg. Med. Chem. Lett. 2006, 16, 1207) gave the title compound. Colorless gum, MS: m/e=263.1 (MH+).
Reaction SMILES: COC1CC2CC[C@H]3[C@H]4[C@@](CCC)(C(=O)CC4)CC[C@@H]3C=2CC=1.C([Mg]Br)C=C.[CH2:29]([C@@:32]1([OH:54])[C@:40]2([CH2:41][CH2:42][CH3:43])[C@H:35]([C@@H:36]3[CH2:51][CH2:50][C:49]4[CH2:48][C:47]([O:52]C)=[CH:46][CH2:45][C:44]=4[C@H:37]3[CH2:38][CH2:39]2)[CH2:34][CH2:33]1)[CH:30]=[CH2:31].Cl.C(O)(C)C.O>>[CH2:29]([C@@:32]1([OH:54])[C@:40]2([CH2:41][CH2:42][CH3:43])[C@H:35]([C@@H:36]3[CH2:51][CH2:50][C:49]4[C@H:44]([CH2:45][CH2:46][C:47](=[O:52])[CH:48]=4)[C@H:37]3[CH2:38][CH2:39]2)[CH2:34][CH2:33]1)[CH:30]=[CH2:31]
Reactant: C=CC[C@]1(O)CC[C@H]2[C@@H]3CCC4=C(CC=C(OC)C4)[C@H]3CC[C@@]21CCC
Agent: C=CC[Mg]Br
Agent: CCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(OC)=CC4
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: C=CC[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CCC

Procedure:
Treat dl-3-methoxy-13-propylgona-2,5(10)-dien-17-one (2.0 g) with allyl magnesium bromide to obtain a glass that is a mixture of dl-17α-allyl-3-methoxy-13-propylgona-2,5(10)-dien-17-ol (minor component) and the Δ5(10) -3-keto and Δ4 -3-keto compounds (major component). Hydrolyze the mixture (in two portions) with hydrochloric acid-isopropanol-water, then chromatograph and crystallize the resultant crude product to obtain the title compound (22% from the starting material), m.p. 135°-137°; ultraviolet absorption peak at 241.5 mμ (ε17,470), infrared maxima at 2.95 μ (OH), 6.03 μ, 6.18 μ (α,β-unsaturated carbonyl), 10.93 μ (R-CH=CH2).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.NC1C(C(OCC)=O)=NC([C:20]2[CH:21]=[N:22][N:23]([CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:24]=2)=CC=1>>[NH2:1][C:2]1[C:3]([C:9]([NH:11][CH3:12])=[O:10])=[N:4][C:5]([C:20]2[CH:21]=[N:22][N:23]([CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(-c2cnn(CCCCO)c2)ccc1N
Reactant: CNC(=O)c1nc(Br)ccc1N
Product: CNC(=O)c1nc(-c2cnn(CCCCO)c2)ccc1N
Yield: 98 %

Procedure:
Prepared analogously to Compound 6D using ethyl 3-amino-6-[1-(4-hydroxybutyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate (Compound 15D, 0.211 g, 0.69 mmol) to afford 196 mg of the title compound (98%). 1H NMR (400 MHz, CDCl3) δ 8.12 (br. s., 1H), 7.87 (s, 1H), 7.81 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 5.94 (br. s., 2H), 4.23 (t, J=6.9 Hz, 2H), 3.70 (q, J=5.9 Hz, 2H), 3.03 (d, J=5.1 Hz, 3H), 2.03 (quin, J=7.3 Hz, 2H), 1.60-1.67 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[C:33]1=[O:41].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:38]([C:34]5[C:33](=[O:41])[N:32]([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[CH3:25])[CH:37]=[CH:36][CH:35]=5)=[O:39])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1ccccc1-n1cccc(C(=O)O)c1=O
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1-n1cccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c1=O
Yield: 53.7 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.613 mmol), 1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (169 mg, 0.735 mmol), N,N-dimethylformamide (2 mL), N,N-diisopropylethylamine (211 μL, 1.23 mmol) and HATU (280 mg, 0.735 mmol) and in the same manner as in Example 24, the title compound (177 mg, 54%) was obtained as pale-yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[C:20]4[CH:19]=[C:18]([O:22][CH:23]([C:35]5[S:36]C=C[CH:39]=5)CNC(=O)OCC[Si](C)(C)C)[C:17]([O:40][CH3:41])=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:11]([CH3:42])[C:10]2=[O:43])=[C:5]([F:44])[CH:4]=1)#[N:2].FC1C=C(C=CC=1N1C2C3C=C(O)C(OC)=CC=3N=CC=2N(C)C1=O)[C:49]#[N:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.S1C(CO)=CN=C1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:44][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N:9]1[C:21]2[C:20]3[CH:19]=[C:18]([O:22][CH2:23][C:35]4[S:36][CH:49]=[N:50][CH:39]=4)[C:17]([O:40][CH3:41])=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]([CH3:42])[C:10]1=[O:43])[C:1]#[N:2]
Reactant: COc1cc2ncc3c(c2cc1O)n(-c1ccc(C#N)cc1F)c(=O)n3C
Reactant: COc1cc2ncc3c(c2cc1OC(CNC(=O)OCC[Si](C)(C)C)c1cccs1)n(-c1ccc(C#N)cc1F)c(=O)n3C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: OCc1cncs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2ncc3c(c2cc1OCc1cncs1)n(-c1ccc(C#N)cc1F)c(=O)n3C

Procedure:
For the preparation, see also synthesis of 2-trimethylsilanylethyl {2-[1-(4-cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yloxy]-2-thiophen-2-ylethyl}carbamate under Example 3b: 3-fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (63 mg, 173 μmol), triphenylphosphine (polymer-bound) (294 mg, 1.12 mmol), thiazol-5-ylmethanol (62 mg, 540 μmol), diisopropyl azodicarboxylate (166 μl, 845 μmol) in tetrahydrofuran (7 ml) were reacted, giving 3-fluoro-4-[7-methoxy-3-methyl-2-oxo-8-(thiazol-5-ylmethoxy)-2,3-dihydroimidazo-[4,5-c]quinolin-1-yl]benzonitrile (15 mg, 32.5 μmol) as solid. MS: 462.0 (M+H+), TLC (HPTLC): Rf=0.44 (ethyl acetate/ethanol 2:1, parts by volume).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[H-].[Na+].C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>C(N(CC)CC)C>[N:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][N:5]=2)[CH:10]=[N:11][CH:2]=1
Reactant: Clc1ncc2nccnc2n1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: c1cnc2ncncc2n1

Procedure:
Treatment of chloro-pteridine V′ with nuclephile R7LY, in the presence of a base, such as sodium hydride, potassium carbonate, triethylamine, and diisopropylethylamine, and optionally using a catalyst such as Pd(0), affords Pteridine compound VI′. Suitable solvent for this reaction includes chloroform, methylene chloride, toluene, and tetrahydrofuran.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)=[O:9].[BH4-].[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CC(O)C>[CH3:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[CH:8]([C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)[OH:9]
Reactant: Cc1csc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CC(C)O
Product: Cc1csc(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1C

Procedure:
A solution of (3,4-dimethylthien-2-yl)-1-trityl-imidazol-4-yl methanone, C5, (3.4 g, 0.0075 mol) and sodium borohydride in 50 mL of 2-propanol was heated at reflux for 2 h. After cooling, 3N hydrochloric acid solution was added to the reaction mixture followed by 10% aqueous sodium carbonate solution. The mixture was concentrated under reduced pressure and the resulting solution was extracted twice with chloroform. The chloroform extracts were combined, dried (Na2SO4), and concentrated. The residue was recrystallized from ethyl acetate with a small amount of chloroform to give a white solid. The mother liquor was concentrated to give a second crop of the desired (3,4-dimethylthien-2-yl)-1-trityl-imidazol-4-yl-methanol, D5. The 1H NMR in CDCl3 supported the assigned structure. ##STR42##
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([C@@H:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][C@H:21]3[OH:41])C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1>C(O)C.Cl.C(O)C>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][C@@H:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:40])[CH2:22][C@H:21]3[OH:41])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1cnc2ccc(=O)n(CCN3CC[C@@H](N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)[C@H](O)C3)c2c1
Agent: Cl
Solvent: CCO
Product: COc1cnc2ccc(=O)n(CCN3CC[C@@H](NCc4cc5c(cn4)OCCO5)[C@H](O)C3)c2c1
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 75 mg of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)((3R,4R)-3-hydroxy-1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 3 mL of ethanol, 3.0 mL of a hydrogen chloride/ethanol solution was added at room temperature. The mixture was stirred at the same temperature for 1 hour, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the resultant residue, and the solid was filtered off. To the solid, chloroform and water were added, and the aqueous layer was separated. The aqueous layer was charged with chloroform and adjusted to pH 12 with a 1 mol/L aqueous sodium hydroxide solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 45 mg of 1-(2-((3R,4R)-4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-3-hydroxypiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:31][NH:32][C:33]([NH:35][OH:36])=[NH:34].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:31][NH:32][C:33](=[NH:34])[NH:35][OH:36])[CH2:9]1
Reactant: N=C(NN)NO
Reactant: Cc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1ccccc1Cl)C2
Temperature: 90 °C
Reaction time: 3 h
Yield: 166.3 %

Procedure:
A mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (679 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (917 mg) and concentrated hydrochloric acid (0.3 ml) in ethanol (10 ml) was stirred at 90° C. (bath temperature) for 3 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (40 ml), tetrahydrofuran (30 ml) and 0.2 N sodium hydroxide (50 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (20 ml) and water (15 ml, thrice). To the upper layer was added 2 N hydrochloric acid (2.5 ml), and the mixture was concentrated under reduced pressure. To the residue was added ethanol (10 ml), and the mixture was stirred at 900° C. (bath temperature) for 3 hours and cooled to give crystals, which were filtered to give 7-(2-chlorophenyl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 106) (790 mg) as pale yellow crystals.