Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCC(N[C@H](C(O)=O)CC1C=CC(O)=CC=1)=O.[CH2:18]([O:20][C:21](=[O:32])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[NH2:23])[CH3:19].[Cl:33][CH2:34][C:35](Cl)=[O:36]>>[CH2:18]([O:20][C:21](=[O:32])[C@H:22]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1)[NH:23][C:35](=[O:36])[CH2:34][Cl:33])[CH3:19]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: NCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CCl

Procedure:
A process for producing N-glycyl-L-tyrosine is disclosed in Berichte der Deutschen Chemischen Gesellschaft, p. 2486 (1904). In the process, L-tyrosine is subjected to a reaction with 1.1 equivalents of chloroacetyl chloride and an aqueous solution of sodium hydroxide to obtain N-chloroacetyl-L-tyrosine, which is then made to react with aqueous ammonia to prepare N-glycyl-L-tyrosine. This process gives N-chloroacetyl-L-tyrosine, which is an intermediate for the synthesis of N-glycyl-L-tyrosine, in a 50% yield. The above literature also discloses a process in which L-tyrosine ethyl ester is made to react with 1.0 equivalent of chloroacetyl chloride to form N-chloroacetyl-L-tyrosine ethyl ester, which is then hydrolyzed to prepare N-chloroacetyl-L-tyrosine. In this process, the overall yield of N-chloroacetyl-L-tyrosine based on L-tyrosine ethyl ester is 91%, and that based on L-tyrosine is 77% as the yield in the step of conversion into ethyl ester from L-tyrosine is 85%. The process for producing N-glycyl-L-tyrosine via L-tyrosine ethyl ester is thus advantageous in respect of yield over the process in which L-tyrosine is directly chloroacetylated. However, when applied to the production on an industrial scale, the former process which requires the steps of esterification and hydrolysis is inefficient compared with the latter process requiring a smaller number of steps.
Reaction SMILES: ClC1N=C2C(N=C[N:8]2[CH:11]2[CH2:15]C(N3C=C(CC)N=N3)[CH:13](O)[CH:12]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:47]1([CH:53]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH2:54][NH:55][C:56]2[N:64]=[C:63]([NH:65][CH2:66][CH2:67]N3CCCCC3)[N:62]=[C:61]3[C:57]=2[N:58]=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3C=[C:82]([CH2:84]O)[CH:81]=[N:80]3)[C@@H:76]([OH:86])[C@H:75]2[OH:87])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C1(N)CC[CH:97]([NH2:100])CC1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH2:8][CH:11]1[CH2:15][CH2:67][CH:66]([NH:65][C:63]2[N:62]=[C:61]3[C:57]([N:58]=[CH:59][N:60]3[C@@H:74]3[CH2:78][C@H:77]([N:79]4[N:80]=[C:81]([CH2:82][CH3:84])[CH:97]=[N:100]4)[C@@H:76]([OH:86])[C@H:75]3[OH:87])=[C:56]([NH:55][CH2:54][CH:53]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)[N:64]=2)[CH2:13][CH2:12]1
Reactant: NC1CCC(N)CC1
Reactant: CCc1cn(C2CC(n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C(O)C2O)nn1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(N)CC5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from 3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA9) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 461 by replacing 1-(2-amino-ethyl)piperidine with cyclohexane-1,4-diamine. MS (ES+) m/e 623.43 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2].[OH-].[K+].[CH3:19][C:20]1[CH:25]=[N:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1>CN1CCCC1=O.O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][N:24]=3)[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc(C)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1ccc2c(c1)c1c(n2CCc2cnc(C)cn2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.8 %

Procedure:
To a solution of 8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.054 g. 0.25 mmol) in N-methyl 2-pyrolidone (2.0 mL) was added powdered potassium hydroxide (0.112 g, 0.002 mol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrazine (0.033 g, 0.75 mmol) was added and stirred for further 1 h. at 60 deg C. After completion (TLC), reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% McOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as yellow oil (0.05 g, 60% yield). 8-Ethyl-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.05 g, 0.000149 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.019 g, 0.000149 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.035 g, 50% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([NH2:15])=[C:9]([N+:12]([O-])=O)[CH:10]=2)[C:5](=[O:16])[NH:4][CH2:3]1>[Pd].CO>[CH3:1][C:2]1([CH3:17])[C:11]2[CH:10]=[C:9]3[NH:12][C:10]([C:11]4[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=4)=[N:15][C:8]3=[CH:7][C:6]=2[C:5](=[O:16])[NH:4][CH2:3]1
Reactant: CC1(C)CNC(=O)c2cc(N)c([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)CNC(=O)c2cc3nc(-c4ccncc4)[nH]c3cc21
Reaction time: 1 h

Procedure:
5 g. (20.4 mmole) 4,4-dimethyl-6-nitro-7-amino-1,2,3,4-tetrahydroisoquinolin-1-one were hydrogenated in 120 ml. methanol in the presence of 0.5 g. 10% palladium on charcoal. After separating off the catalyst, the evaporation residue (4.3 g.) was acylated in 150 ml. methylene chloride and 8.4 ml. triethylamine with 5.4 g. isonicotinic acid chloride hydrochloride. After 1 hour, the evaporation residue is worked up with water and filtered off with suction. The moist residue was subsequently boiled in 100 ml. ethanol and 20 ml. concentrated hydrochloric acid for 24 hours, evaporated, mixed with water and neutralized. After column chromatography (silica gel, elution agent: methylene chloride/methanol saturated with ammonia; 15:1 v/v) and boiling up, there were obtained 2.3 g. (41% of theory) of the title compound; m.p. above 300° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:11].Br[C:13]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>C(O)(C)C.CN1CCOCC1.[Cu].[Cu]I>[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:13]3[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=[O:16])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:5]1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: Cn1ncc2c(N)cccc21
Agent: [Cu]
Agent: [Cu]I
Solvent: CC(C)O
Solvent: CN1CCOCC1
Product: Cn1ncc2c(Nc3c(C(=O)O)cccc3[N+](=O)[O-])cccc21
Yield: 5 %

Procedure:
A solution of 4-nitroindazole (prepared according to the literature procedures Davies, R. R. J.C.S., 1955, 2412-2423; Porter, H. D. Org. Synth. Collect. Vol I, 20, 73-74.) (2.01 g, 12.3 mmol) was added slowly to a cold (ice/water), stirred suspension of NaH (440 mg, 18.4 mmol) in DMF (20 mL) under N2. The mixture was stirred for 30 min, and a solution of MeI (1.91 g, 13.5 mmol) in DMF (10 mL) was then added. Workup gave 1-methyl-4-nitroindazole (1.79 g, 82%); mp (EtOAc/petroleum ether) 138-139° C. Hydrogenation of this (6.70 g, 37.9 mmol) in absolute EtOH (300 mL) in the presence of Pd/C (1.00 g) gave 4-amino-1-methylindazole (4.23 g, 76%). A mixture of 4-amino-1-methylindazole (4.10 g, 27.9 mmol) and 2-bromo-3-nitrobenzoic acid (6.86 g, 27.9 mmol) were then reacted in a mixture of isopropanol/N-methylmorpholine in the presence of copper powder and CuI as above, giving 2-[(1-methyl-1H-indazol-4-yl)amino]-3-nitrobenzoic acid (439 mg, 5 %); mp (EtOAc/n-hexane) 257-260° C.; Reductive cyclisation of 2-[(1-methyl-1H-indazol-4-yl)amino]-3-nitrobenzoic acid with NaBH4 in 2 M NaOH as above gave 3-methyl-3H-pyrazolo[4,3-a]phenazine-10-carboxylic acid as a dark yellow solid (54%); mp (acetone) 320-323° C. [(CD3)2SO] δ 4.28 (s, 3 H, NCH3), 8.07 (t, J=7.9 Hz, 1 H, H-8), 8.10 (d, J=9.6 Hz 1H, H-4 or H-5), 8.39 (d, J=9.6 Hz 1H, H-4 or H-5), 8.52-8.60 (m, 2H, H-7 and H-9), 8.76 (s, 1 H, H-2), 14.90 (br s, 1 H, COOH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.O.CC(C)([O-])C.[K+].Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[CH:19]1([CH2:18][O:8][C:6]2[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[CH:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrCC1CCCCC1
Reactant: Cc1cc(O)cc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)cc(OCC2CCCCC2)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 5-methylbenzene-1,3-diol H2O (1.0 g, 7.0 mmol) in DMF (15 ml) was added potassium tert-butoxide (0.86 g, 77 mmol). The mixture was stirred at 60° C. for 1 h. To the mixture was added (bromomethyl)cyclohexane (1.2 g, 7.0 mmol). The reaction mixture was stirred at 60° C. for 18 h, concentrated under vacuum, partitioned between water (40 ml) and ethyl acetate (60 ml). Ethyl acetate portion was dried over Na2SO4. Purification by chromatography (10 to 30% EtOAc-hexanes gradient) gave 3-(cyclohexylmethoxy)-5-methylphenol (133) as a light yellow solid. Yield (0.40 g, 26%): 1H NMR (400 MHz, CDCl3) δ 6.31 (s, 1H), 6.20-6.22 (m, 2H), 4.62 (bs, 1H), 3.69 (d, J=6.4 Hz, 2H), 2.50 (s, 3H), 1.64-1.88 (m, 6H), 1.16-1.34 (m, 3H), 0.98-1.08 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[CH2:5]([O:7][P:8]([O:12]CC)[O:9][CH2:10][CH3:11])[CH3:6]>>[Br:1][CH2:2][CH2:3][P:8](=[O:12])([O:9][CH2:10][CH3:11])[O:7][CH2:5][CH3:6]
Reactant: BrCCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCBr)OCC
Temperature: 65 °C
Yield: 95 %

Procedure:
1,2-dibromoethane (69 ml, 0.8 mol) was poured into a two-necked 150 mL round-bottom flask. Triethylphosphite (34.3 ml, 0.2 mol) was added under stirring and the mixture was then refluxed for 2 hours. The excess of 1,2-dibromoethane was removed by rotary evaporation under gentle warming at 60-70° C. The residue was distilled under reduced pressure (2 mmHg, 95-105° C. or 1 mmHg, 75° C.). Yield 95%.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16](=[O:34])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:33])[NH:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)=[CH:10]2)C.[OH-].[Na+].Cl>C1COCC1.CO>[O:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]1[O:26][NH:25][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]([C:11]1[NH:12][C:13]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH2:6][CH2:5][C:4]([OH:35])=[O:3])=[CH:15][CH:14]=2)=[O:34])=[O:33]
Reactant: CCOC(=O)CCc1ccc2[nH]c(C(=O)NCCCCCCC(=O)NOC3CCCCO3)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc2[nH]c(C(=O)NCCCCCCC(=O)NOC3CCCCO3)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.7 %

Procedure:
3-{2-[6-(Tetrahydro-pyran-2-yloxycarbamoyl)-hexylcarbamoyl]-1H-indol-5-yl}-propionic acid ethyl ester (550 mg, 1.13 mmol) was dissolved in THF/methanol (50 ml/25 ml). 1.4 M NaOH solution (50 ml) was added and the reaction stirred at room temperature for 4 h. The solvent was reduced to ˜50% volume and 1M HCl added to pH 6-7. The mixture was extracted with DCM and further extracted with EtOAc. The combined organic layer was dried, Na2SO4 and the solvent removed in vacuo to give the required product 357 mg (69% yield) as a yellow powder which was used in the next step without further purification. LCMS purity 94%, m/z 460 [M++H]+
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:32][O:33][NH2:34])[N:26]([CH2:27][C:28]([CH3:31])([OH:30])[CH3:29])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1>CN(C=O)C>[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:32][O:33][NH:34][S:9]([CH3:8])(=[O:11])=[O:10])[N:26]([CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1c(CONS(C)(=O)=O)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 4.6 %

Procedure:
Triethylamine (0.634 mL, 4.55 mmol) and methanesulfonyl chloride (0.211 mL, 2.73 mmol) were added to a solution of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 685 mg, 2.27 mmol) in DMF (5 mL). A solid formed immediately. The mixture was stirred for 3.5 hours at room temperature, then additional triethylamine (0.634 mL) and methanesulfonyl chloride (0.211 mL) were added. The reaction mixture was stirred for an additional 1.5 hours, then was partitioned between water (20 mL) and dichloromethane (30 mL). The aqueous layer was extracted with dichloromethane (2×30 mL). The organic layers were combined and allowed to stand overnight at room temperature. Crystals formed and were isolated by filtration to provide 40 mg of N-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}methanesulfonamide. Additional crystals were isolated from the mother liquor after a seed crystal was added. The two crops were combined and dried in a vacuum oven to provide 160 mg of N-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}methanesulfonamide as pale yellow crystals, mp 232-234° C.
Reaction SMILES: C([C@H]1COC(=O)N1C(=O)[CH2:15][C@H:16]([C:38]1[CH:42]=[CH:41][O:40][N:39]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH3:26])=[CH:19][CH:18]=1)C1C=CC=CC=1.[OH:44]O.[OH-].[Li+].Cl.C1[CH2:53][O:52]CC1>O>[O:40]1[CH:41]=[CH:42][C:38]([C@H:16]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH:25]([O:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=3)[CH3:26])=[CH:21][CH:22]=2)[CH2:15][C:53]([OH:52])=[O:44])=[N:39]1
Reactant: C1CCOC1
Reactant: OO
Reactant: CC(COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(COc1ccc([C@H](CC(=O)O)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a solution of the oxazolidinone (48.2) (39.0 mg, 0.066 mmol) dissolved in THF (3 mL), was added a 30% hydrogen peroxide solution (74 μL, 0.66 mmol) followed by a 2 M lithium hydroxide solution (160 μL, 0.33 mmol). The resulting slurry was stirred for one hour. The reaction mixture was then diluted with water and acidified with hydrochloric acid to pH ˜3. The mixture was then extracted with EtOAc (1×20 mL), and the organic layer was washed with an acidic sodium sulfite solution (2×15 mL) and brine (1×15 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 48 (7.5 mg). MS ESI (pos.) m/e: 436.1 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.33 (1 H, d, J=1.6 Hz), 7.51 (2 H, d, J=8.6 Hz), 7.12 (2 H, d, J=9.0 Hz), 6.97 (2 H, d, J=8.6 Hz), 6.80 (2 H, d), 6.14 (1 H, d, J=1.6 Hz), 4.43 (1 H, t, J=7.8 Hz), 4.12 (2 H, t, J=6.3 Hz), 4.05 (2 H, t, J=6.3 Hz), 3.08 (1 H, dd, J=16.4, 8.2 Hz), 2.83 (1 H, dd, J=16.6, 7.2 Hz), 2.06-2.19 (2 H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:32])[CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[CH:25][CH:26]=2)[CH2:21]1)=O.COC1C(OC)=CC=C2C=1CCC(NC)C2>C(O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][NH:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:32])[CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[CH:25][CH:26]=2)[CH2:21]1
Reactant: COc1ccc2c(c1)CC(N(C)CCCNC(=O)Cc1cc(OC)c(OC)cc1N)CC2
Agent: CNC1CCc2c(ccc(OC)c2OC)C1
Solvent: CCO
Product: COc1ccc2c(c1)CC(N(C)CCCNCCc1cc(OC)c(OC)cc1N)CC2

Procedure:
The title compound here is prepared from 1-[2(-2-amino-4,5-dimethoxyphenyl)-1-oxo-ethylamino]-3-[N-methyl-N-(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-propane (6.73 g, 0.0153 mol) analogously to Example R(e). Yield: 4.2 g. Rf value: 0.2 (alumina, eluant: 95 parts by volume of methylene chloride+5 parts by volume of ethanol).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:13]([CH2:14]O)=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:16])[CH:10]=2)[N:5]=1)[CH3:2].S(Cl)([Cl:19])=O>C(Cl)Cl>[ClH:19].[Cl:19][CH2:14][C:13]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH3:16])=[CH:8][CH:7]=2
Reactant: O=S(Cl)Cl
Reactant: CCNc1nc2ccc(C)cc2cc1CO
Solvent: ClCCl
Product: CCNc1nc2ccc(C)cc2cc1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of (2-(ethylamino)-6-methylquinolin-3-yl)methanol RBO 35160 (460 mg, 2.13 mmol) in CH2Cl2 (30 mL) in a round-bottomed flask equipped with a magnetic stirrer was added thionyl chloride (1.55 mL, 21.3 mmol). The mixture was stirred for 2 h at RT, evaporated under vacuum at 45° C., coevaporated twice with CH2Cl2 to remove SOCl2 to afford 3-(chloromethyl)-N-ethyl-6-methylquinolin-2-amine hydrochloride RBO 35162 as a yellow solid (520 mg, 90% yield).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]
Reactant: Nc1cc(F)ccc1F
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(Nc1cc(F)ccc1F)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 66.8 %

Procedure:
2,5-difluoroaniline (0.074 mL, 0.73 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (0.09 g, 0.18 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(2,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.055 g, 66%) as a white solid. Mass Spectrum: M+H+ 458. NMR Spectrum (DMSOd6): 1.57 (d, 3H), 2.72 (bs, 3H), 2.94 (bs, 3H), 3.51-3.64 (m, 4H), 3.71-3.78 (m, 4H), 5.02-5.11 (m, 1H), 5.61 (s, 1H), 6.19-1.33 (m, 2H), 6.43 (d, 1H), 7.01-7.09 (m, 1H), 7.60 (d, 1H), 7.79 (d, 1H).
Reaction SMILES: [C@@H:1]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C[Si](Cl)(C)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34](Cl)=[O:35])[CH:30]=[CH:31][CH:32]=1.[NH3:37]>N1C=CC=CC=1.O>[N:37]#[N:9].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34]([C@@:1]2([N:9]3[C:19]4[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=4[N:11]=[CH:10]3)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: N
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1cccc(CC(=O)[C@]2(n3cnc4c(=O)[nH]c(N)nc43)C[C@H](O)[C@@H](CO)O2)c1
Product: N#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To dry 2'-deoxyguanosine (1) (14.2 g, 50 mmoles) in 300 ml of dry pyridine at 0° C. was added trimethylsilyl chloride (33 ml, 250 mmoles) and the mixture stirred at 0° C. for 1 hour. 3-Methoxyphenylacetyl chloride (40 ml, 250 mmoles) was added and the solution maintained at room temperature for 15 hours. The reaction mixture was then cooled in an ice bath and 50 ml of cold water was added. After 30 minutes, 50 ml of 29% aqueous ammonia was added and the mixture stirred for 30 minutes. The solution was then evaporated to near dryness and the residue dissolved in 400 ml water and 400 ml methylene chloride in a separating funnel. The product crystallized out of the aqueous solution upon extraction with CH2Cl2 was filtered off, washed with CH2Cl2 (3×50 ml) and ether (3×50 ml) and air dried to yield 15.56 g (75%) of N2 -(3-methoxyphenylacetyl)-2'-deoxyguanosine (2b), as confirmed by spectroscopic and elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][C:14]=2[C:21]([F:24])([F:23])[F:22])[N:8]=1)=[O:5].P(Br)(Br)[Br:31]>C(Cl)Cl.C(=O)([O-])O.[Na+]>[Br:31][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:9]2[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:28][CH:27]=[CH:26][C:25]=3[F:29])=[N:8]2)=[C:14]([C:21]([F:24])([F:23])[F:22])[CH:15]=1
Reactant: BrP(Br)Br
Reactant: O=C(Nc1ccn(Cc2ccc(CO)cc2C(F)(F)F)n1)c1c(F)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccn(Cc2ccc(CBr)cc2C(F)(F)F)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,6-difluoro-N-(1-{[4-(hydroxymethyl)-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Example 44) (0.119 g, 0.289 mmol) in DCM (6.5 ml) in an ice-water bath under nitrogen was added phosphorus tribromide (0.027 ml, 0.289 mmol, Aldrich). The cloudy mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was diluted with saturated sodium hydrogen carbonate aqueous (15 ml) and ice (15 ml). The biphasic mixture was diluted with DCM (25 ml). The phases were separated and the aqueous phase washed with DCM (20 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound a colourless gum (98 mg). LCMS: (System 4) MH+=475.9, tRET=3.06 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([O:22]CC)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].Cl>C(O)C.O1CCCC1.[OH-].[Na+]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([OH:22])=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)O
Temperature: 50 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To a solution of ethyl 2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (C4, 0.90 g) in ethanol (10 mL) and tetrahydrofuran (5 mL), 2.0 mol/L aqueous sodium hydroxide (2.8 mL) was added at room temperature, and the mixture was stirred at 50° C. for 5 hours. The reaction mixture was cooled to room temperature, and then 1.0 mol/L aqueous hydrochloric acid was added to the reaction mixture until the mixture became acidic. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (C5, 738 mg).