Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[N:3]=[CH:2]1.[C:15](=[O:18])([O-])[O-].[K+].[K+].[CH3:21][N:22]([CH:24]=[O:25])C>>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:4]2[N:3]=[CH:2][N:1]([CH2:5][CH2:4][CH2:6][CH2:21][N:22]3[C:24](=[O:25])[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:15]3=[O:18])[CH:5]=2)=[CH:7]1
Reactant: O=C([O-])[O-]
Reactant: c1ccc2c(-c3c[nH]cn3)c[nH]c2c1
Reactant: CN(C)C=O
Agent: [K+]
Product: O=C1c2ccccc2C(=O)N1CCCCn1cnc(-c2c[nH]c3ccccc23)c1
Reaction time: 1 h

Procedure:
7.9 g of product of Stage A, 50 ml of DMF and 11.93 g of potassium carbonate are agitated for 15 minutes at 110° C., dried in an oven under phosphoric anhydride. A solution of 15.83 g of N-(4-bromobutyl)phthalimide in 30 ml of DMF is added dropwise at ambient temperature. Agitation is carried out for one hour at 110° C. The reaction medium is poured into sodium acid phosphate, followed by evaporation under reduced pressure. 19.11 g of crude product is obtained which is purified on silica eluting with a methylene chloride-methanol-ammonium hydroxide mixture 97-3-05. 4.58 g of sought product is obtained.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](=[O:13])[C:11]2[CH:10]=[C:9]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:8]3=[CH:7][C:6]=2[CH2:5]1)[CH3:3].[Cl:19][CH2:20][CH2:21][CH2:22][CH2:23][S:24][C:25]1[N:26]([CH3:41])[C:27]([C:30]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:31]=2[CH:32]=[CH:33][C:34]([CH3:40])=[N:35]3)=[N:28][N:29]=1>>[ClH:19].[CH3:3][CH:2]([N:4]1[C:12](=[O:13])[C:11]2[CH:10]=[C:9]3[CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH2:22][CH2:23][S:24][C:25]4[N:26]([CH3:41])[C:27]([C:30]5[CH:39]=[CH:38][CH:37]=[C:36]6[C:31]=5[CH:32]=[CH:33][C:34]([CH3:40])=[N:35]6)=[N:28][N:29]=4)[CH2:17][CH2:18][C:8]3=[CH:7][C:6]=2[CH2:5]1)[CH3:1]
Reactant: Cc1ccc2c(-c3nnc(SCCCCCl)n3C)cccc2n1
Reactant: CC(C)N1Cc2cc3c(cc2C1=O)CCNCC3
Product: Cc1ccc2c(-c3nnc(SCCCCN4CCc5cc6c(cc5CC4)C(=O)N(C(C)C)C6)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-(1-methylethyl)-3,5,6,7,8,9-hexahydroazepino[4,5-f]isoindol-1(2H)-one (80 mg) and 5-{5-[(4-chlorobutyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (135 mg) and was obtained as a colourless slightly hygroscopic solid (90 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[CH2:11][C:12]([OH:14])=O.C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]1[CH:28]=[C:29]([NH2:56])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]=[CH:45][N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH:47]=3)[S:42][C:35]=12.C(Cl)CCl>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]([NH:56][C:12](=[O:14])[CH2:11][C:10]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:15])[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]2[CH:40]=[C:41]([C:43]3[N:44]=[CH:45][N:46]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:54])([CH3:53])[CH3:55])[CH:47]=3)[S:42][C:35]=12
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cn(COCC[Si](C)(C)C)cn4)sc23)c(F)c1
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
To a solution of the acid 27 (59 mg, 2 eq, 0.28 mmol) and HOBT (19 mg, 1 eq, 0.14 mmol) in DMF (3 ml) was added amine 104 (64 mg, 0.14 mmol) and the reaction mixture was stirred for 10 mins. EDC (54 mg, 2 eq, 0.28 mmol) was added and the reaction mixture was stirred at RT overnight. The solvents were removed and the residue was partitioned between EtOAc and water. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (20% acetone in hexane to 100% acetone) afforded title compound 105 (53 mg, 58% yield). MS (m/z): 648.2 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6](=O)[C:7](=[N:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8](=O)[CH3:9])([CH3:4])([CH3:3])[CH3:2].NC1C=CC=CC=1.C(NC(=O)CC(C)=O)(C)(C)C.O.[NH2:39][NH2:40]>C(O)C>[C:1]([NH:5][C:6]1[C:7](=[N:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([CH3:9])=[N:40][N:39]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C(=NNc1ccccc1)C(=O)NC(C)(C)C
Reactant: NN
Agent: CC(=O)CC(=O)NC(C)(C)C
Solvent: CCO
Solvent: O
Solvent: Nc1ccccc1
Product: CC1=NN=C(NC(C)(C)C)C1=NNc1ccccc1
Temperature: 25 °C
Yield: 36.9 %

Procedure:
The title compound was prepared using 100 mg (0.4 mmol) of N-tert-butyl-3-oxo-2-(phenylhydrazono)butyramide which was synthesized using aniline (1.7 mmol) and N-tert-butyl acetoacetamide (393 mg, 2.5 mmol). Hydrazine hydrate (2.3 mmol) was added to a solution of N-tert-butyl-3-oxo-2-(phenylhydrazono)butyramide in ethanol. Very little solid had formed after heating the reaction at 75° C. for 1 hour, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was recrystallized from ethanol/water. The resulting solid was isolated by filtration and dried to yield 38 mg (43%) of the title compound as a yellow solid. 1H NMR (ppm, 200 MHz, CDCl3) δ 1.42 (s, 9H), 2.20 (s, 3H), 5.35 (br s, 1H), 6.95 (t, 1H), 7.15-7.35 (m, 4H), 9.95 (br s, 1H); IR (cm−1, KBr pellet): 3368 (w), 3197 (w), 3038 (w), 2973 (w), 2928 (w), 1631 (m), 1602 (m), 1565 (m), 1516 (s), 1498 (s), 1391 (w), 1366 (m), 1225 (m), 1187 (w), 1166 (w), 1119 (w), 1074 (w), 1059 (w), 949 (w), 895 (w), 775 (w), 748 (w), 691 (m), 561 (w); MS (m/z, ES+): 276.2 (M+18, 5%), 259.2 (M+1, 1%), 203.1 (M-55, 5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].[Li+].[OH-]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)CCCCc1cc(Cl)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCCc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.9 %

Procedure:
Methyl 5-(2,5-Dichlorophenyl)pentanoate (1.10 g, 4.2 mmol) was dissolved in 20 ml THF and 7 mL methanol. 1 N LiOH (12 mL) was added dropwise and the reaction was stirred at room temperature for 2 days. The reaction was worked-up by acidification with 2 N HCl and removal of most of the THF and methanol on a rotary evaporator followed by extraction of the aqueous residue with ethyl acetate. The organic phase was washed with water and saturated brine, dried over sodium sulfate and concentrated to a residue. Flash chromatography (silica gel; hexane/toluene (19/1) with 1% acetic acid) of the residue gave 725 mg (70%) of a white solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.6 %

Procedure:
To a solution of 4-phenylimidazole (500 mg, 3.47 mmol) in 5 mL DMF, were added TEA (508 μL, 3.64 mmol) and trityl chloride (1.06 g, 3.82 mmol). The mixture was stirred at rt for 15 h, then was poured into 50 mL H2O. The precipitate was collected by filtration and sucked dry, then was suspended in 20 mL Et2O. The suspension was filtered, rinsed with 5 mL Et2O, then vacuum dried to afford 974 mg of Intermediate 8.1 as a white solid.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9](COS(C)(=O)=O)=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[CH3:37]N(C)C=O>>[C:33]([O:32][C:30]([N:24]1[CH2:29][CH2:28][N:27]([C:9]2[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:6]=[C:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:8]=2[CH3:37])[CH2:26][CH2:25]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CN(C)C=O
Reactant: CC(C)Cn1nc(-c2ccccc2)cc(COS(C)(=O)=O)c1=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Cc1c(-c2ccccc2)nn(CC(C)C)c(=O)c1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 83.5 %

Procedure:
Following the procedure of Example 1(10), 2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted in N,N-dimethylformamide as a solvent to yield the title compound as a yellow oil (yield: 83.5%).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.C(O)CC>N1C=CC=CC=1>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:1](=[O:10])[CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: c1ccncc1
Solvent: CCCO
Product: O=C(C=Cc1ccccc1)Nc1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
Cinnamoyl chloride (7.3 g) is added to a suspension of 2-amino-7-chloro-1,8-naphthyridine (7.2 g) in pyridine (80 cc). After stirred for 2 hours at 20° C., the suspension obtained is poured into distilled water (500 cc). The suspension is filtered, washed with water (3×50 cc) and dried at 50° C. under reduced pressure (0.07 kPa). The solid obtained (10.6 g; m.p. 263° C.) is dissolved in boiling 1-propanol (1200 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with 1-propanol (3×50 cc), diethyl ether (2×50 cc) and dried at 50° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3-phenylpropenamide (11.4 g), m.p. 263° C., is obtained.
Reaction SMILES: [OH:1][CH:2]([CH3:7])[CH2:3][CH2:4][C:5]#[N:6].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C1C=CC=CC=1>[CH3:15][S:16]([O:1][CH:2]([CH3:7])[CH2:3][CH2:4][C:5]#[N:6])(=[O:18])=[O:17]
Reactant: CC(O)CCC#N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(CCC#N)OS(C)(=O)=O
Reaction time: 0.33 h

Procedure:
To a cooled (ice bath) stirred solution of 4-hydroxypentanonitrile (18.8 g, 0.19 mol) in benzene (100 ml) and triethyl amine (20 g, 0.198 mol) was added dropwise a solution of methanesulphonyl chloride (22.34 g 0.195 mol) in benzene (20 ml) over a period of 40 min. After addition was complete the stirring was continued for 20 min at room temperature. The solid (TEA.HCl) was filtered off and washed with benzene. The filtrate and washings were combined and concentrated in vacuo to give 37.7 g of the title compond containing approximately 12% of benzene: 1Hmr (CDCl3) δ: 7.38 (3H, benzene), 4.82 (1H, q, J=13 Hz), 3.1 (3H, s), 2.48 (2H, dt), 2.0 (2H, dt) and 1.46 ppm (3H, t, J=13 Hz); ir (neat) νmax : 2243 cm-1.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH:52]12[CH2:61][CH:56]3[CH2:57][CH:58]([CH2:60][CH:54]([CH2:55]3)[CH:53]1[NH:62][CH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)[CH2:59]2>CN(C=O)C.O>[CH:54]12[CH2:55][CH:56]3[CH2:57][CH:58]([CH2:59][CH:52]([CH2:61]3)[CH:53]1[NH:62][CH:63]1[CH2:68][CH2:67][N:66]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:65][CH2:64]1)[CH2:60]2
Reactant: C1CC(NC2C3CC4CC(C3)CC2C4)CCN1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(NC2C3CC4CC(C3)CC2C4)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 81.8 %

Procedure:
DIPEA (150 mg, 3.5 mmol) was added to a stirred solution [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (150 mg, 0.53 mmol) in DMF (4 mL) followed by HOBt (82 mg, 0.61 mmol) and EDCI.HCl (270 mg, 1.4 mmol). After 2 minutes of stirring, adamantan-2-yl-piperidin-4-yl-amine dihydrochloride (150 mg, 0.59 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water and the precipitate was filtered to afford 200 mg (81.63% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(adamantan-2-ylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 462.28, 91.77%. 1H NMR (300 MHz, DMSO-d6): δ8.2-8.0 (bs, 1H), 7.82-7.76 (d, 2H), 7.5-7.42 (t, 2H), 7.4-7.34 (t, 1H), 7.2-7.1 (bs, 1H), 4.3-4.1 (m, 3H), 3.8 (d, 1H), 3.1 (t, 1H), 2.9-2.7 (m, 3H), 2.1 (d, 2H), 1.9-1.6 (m, 1H), 1.4-1.3 (d, 3H), 1.2-1.1 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)=[CH:9][CH:8]=1)C.[OH-].[Li+]>O1CCCC1.C(O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:14]([O:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:26])=[O:3])=[CH:12][CH:11]=2)[CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)COc1ccc(OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCC(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 4-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)phenoxyacetic acid ethyl ester (2.5 g) in a mixture of tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1N aqueous lithium hydroxide solution (7.5 ml) with ice-cooling, and the mixture was stirred at room temperature for 30 min. After completion of the reaction, the solvent was evaporated and to the obtained residue were added ice water and 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound(2.30 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].S(Cl)([Cl:17])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)O)cc1S(N)(=O)=O
Product: Cc1ccc(C(=O)Cl)cc1S(N)(=O)=O

Procedure:
4-Methyl-3-sulfamoyl-benzoic acid (2 g, 10 mmol) is added to thionyl chloride (15 mL) and heated at reflux for 3 hours. Hexanes are added to the cooled solution and an oil forms. The hexanes are decanted and the oil is dissolved in methylene chloride and washed with hexanes. The solvent is removed under reduced pressure and the crude oil used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][OH:11])[C:6]=2[CH:12]=1.C12([C:23]3[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=3OC)[CH:26]=[O:27])CC3CC(CC(C3)C1)C2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][O:11][C:30]3[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=3)[C:6]=2[CH:12]=1
Reactant: OCc1coc2ccc(Cl)cc12
Reactant: COc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Product: O=Cc1ccc(OCc2coc3ccc(Cl)cc23)cc1
Yield: 9 %

Procedure:
When the product of Step A was substituted for 3-(1-admantanyl)-4-methoxy benzaldehyde in Example 32, Step B, the similar procedure afforded the title compound in 9% yield, as pale paste. 1H-NMR (CDCl3) 9.89 (s, 1H); 7.84 (d, 2H, J=8.74 Hz); 7.72 (s, 1H); 7.60 (d, 1H, J=2.07 Hz); 7.41 (d, 1H, J=8.76 Hz); 7.28 (dd, 1H, J=8.75, 2.09 Hz); 7.09 (d, 2H, J=8.73 Hz); 5.23 (s, 2H).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]([F:18])([F:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].S(C1C=CC(C)=CC=1)(OC)(=O)=O>CN(C)C=O>[CH3:1][O:16][C:9]([C:8]([F:17])([F:18])[F:7])=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(OC)C(F)(F)F
Temperature: 20 °C
Yield: 60.1 %

Procedure:
Cesium carbonate (132.8 g) was added to a mixture of ethyl 4,4,4-trifluoroacetoacetate (75.0 g) and dimethylformamide (400 ml). The reaction mixture was heated to 20° C. for 30 minutes. A mixture of methyl tosylate (83.4 g) and dimethylformamide (150 ml) was added to the resulting reaction mixture within 40 minutes. The mixture was heated for 3 hours and cooled to room temperature. Upon dilution with water (800 ml) the reaction mixture was extracted with diethyl ether three times. The combined organic phases were washed with water and dried. The mixture was concentrated and the residue distilled under reduced pressure to yield the product as a clear liquid (48.5 g, 60%) with a boiling point of 62-70° C. at 12 mm.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN([CH:9]=[O:10])C.[C:11]1([CH2:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>O>[Cl:3][C:18]([CH3:19])=[C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:9]=[O:10]
Reactant: CC(=O)Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(Cl)=C(C=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.375 mol (35 mL) of POCl3 was added at 0° C. to a 0.45 mol (35 mL) of DMF. At the end of the addition, the mixture was allowed to warm to room temperature and stirred for 1 h. Then it was cooled again to 0° C. and carefully treated with 0.15 mol (20.1 g) of phenylacetone. The resulting reaction mixture was stirred at the same temperature for 1 h. Then it was poured into a mixture of ice and water, added of sodium acetate and extracted with CHC3 (3×50 mL). The organic phase was separated, washed with water until neutral pH, dried over MgSO4 and carefully evaporated off to dryness. The residue was distilled in vacuo, b.p. 90–110° C./0.21 torr.
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[H][H].[CH2:12]([OH:18])[CH2:13][O:14][CH2:15][CH2:16]O>[Pd]>[NH2:3][C:2]1[N:4]=[C:5]([NH2:6])[N:7]=[C:8]([NH:9][CH2:16][CH2:15][O:14][CH2:13][CH2:12][OH:18])[N:1]=1.[NH2:3][C:2]1[N:4]=[C:5]([NH:6][CH2:16][CH2:15][O:14][CH2:13][CH2:12][OH:18])[N:7]=[C:8]([NH:9][CH2:16][CH2:15][O:14][CH2:13][CH2:12][OH:18])[N:1]=1
Reactant: Nc1nc(N)nc(N)n1
Reactant: OCCOCCO
Reactant: [H][H]
Agent: [Pd]
Product: Nc1nc(N)nc(NCCOCCO)n1
Product: Nc1nc(NCCOCCO)nc(NCCOCCO)n1
Reaction time: 2 h

Procedure:
In a stainless steel autoclave of an inner volume of 100 ml, 1.26 g (10 mmol) of melamine, 250 mg of 5% Pd—C catalyst, 250 mg of CuO and 30 ml of diethylene glycol were charged. After the inside of the reaction system was sufficiently substituted with nitrogen gas, 10 kg/cm2 of hydrogen gas was introduced under pressure at normal temperature. Then, the temperature was elevated while stirring, and after the temperature reached 260° C., the reaction was carried out at the same temperature for further 2 hours. After cooling, the reaction mixture was taken out and quantitative analysis of the reaction product was performed under the above analytical conditions. As a result, the reaction conversion rate of the starting material melamine was 38.8% and it was confirmed that there were produced 2,4-diamino-6-(5-hydroxy-3-oxapentylamino) -1,3,5-triazine in a yield of 22.9% and 2-amino-4,6-bis(5-hydroxy-3-oxapentylamino)-1,3,5-triazine in a yield of 3.9%, respectively.
Reaction SMILES: FC(F)(F)C(O)=O.C([S:11][CH2:12][CH:13]([CH2:28][CH2:29][CH2:30][NH2:31])[C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])=[O:15])(=O)C>O.N>[NH2:31][CH2:30][CH2:29][CH2:28][CH:13]([CH2:12][SH:11])[C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])=[O:15]
Reactant: CC(=O)SCC(CCCN)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N=C(N)NCCC[C@H](NC(=O)C(CS)CCCN)C(=O)O

Procedure:
Nα -(2-acetylthiomethyl-5-aminopentanoyl)-L-arginine trifluoroacetate (2 g) is dissolved in a mixture of water (25 ml) and concentrated ammonia (25 ml) and this solution is stored at room temperature for twenty minutes. The solution is concentrated in vacuo to ca. 5 ml and applied to a column of Dowex 50 ion exchange resin (50 ml) in the hydrogen cycle. After washing with water Nα -(5-amino-2-mercaptomethylpentanoyl)-L-arginine is eluted with a pyridine-acetate buffer at pH 6.5.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C:20]([F:29])([F:28])[CH:21]([CH:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)[OH:22]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:25]3[CH2:26][CH2:27][CH:23]([CH:21]([OH:22])[C:20]([F:28])([F:29])[F:19])[CH2:24]3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: OC(C1CCNC1)C(F)(F)F
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: O=C(c1ccc(C2CC2)c(OCC2CC2)n1)N1CCC(C(O)C(F)(F)F)C1
Yield: 48.6 %

Procedure:
In analogy to the procedure described in Example 127 e), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 20 mg, 85.7 μmol) was reacted with 2,2,2-trifluoro-1-(pyrrolidin-3-yl)ethanol hydrochloride (CAN of corresponding free base: 943906-23-8, 21.2 mg, 103 μmol) to obtain the title compound (16 mg, 49%) as colorless liquid, MS (EI): m/e=385.3 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[N:21]=3)[CH2:16][CH:15]2C(O)=O)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=N[C:63]2[CH:64]=[CH:65][CH:66]=N[C:62]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:77][N:78]([CH:80]=[O:81])[CH3:79]>>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[N:21]=3)[CH2:16][CH:15]2[C:80](=[O:81])[N:78]([CH2:79][CH2:66][CH2:65][CH2:64][CH:63]=[CH2:62])[CH3:77])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3ccc(OC)cc3)nc3c(C)c(OC)ccc23)CC1C(=O)O)C(=O)OCC
Reactant: CN(C)C=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-c3ccc(OC)cc3)nc3c(C)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
The acid 134 (723 mg, 1.227 mmol) was dissolved in DMF (25 mL). Diisopropyl ethylamine (633 mg, 4.91 mmol) was added and the reaction mixture was placed on an ice-bath. N-methyl-1-hexen hydrochloride (266 mg, 1.78 mmol) and HATU (676 mg, 1.78 mmol) were added and the mixture was stirred at room temperature for 1 h. The solvent was removed and the residue was partitioned between EtOAc and aqueous sodium bicarbonate. The organic phase was collected and the crude product was purified by column chromatography (silica gel, Heptane/EtOAc 80:20→50:50). Evaporation of the solvent gave the title compound (585 mg, 70%). MS (M+H)+ 685.