Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[ClH:15].Cl.[CH2:17]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:15].[ClH:15].[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C:3]([CH2:2][N:29]1[CH2:30][CH2:31][N:26]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:27][CH2:28]1)=[O:4]
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCN(CC(=O)c2ccc3ccccc3c2)CC1)c1ccccc1
Temperature: 50 °C
Reaction time: 10 h

Procedure:
A mixture of 2-bromo-1-(naphthalen-2-yl)ethanone (0.95 g, 3.8 mmol), N-phenacyl piperazine dihydrochloride (0.89 g, 3.2 mmol) and K2CO3 (1.56 g, 11.2 mmol) in 30 ml of DMF was stirred at 50° C. for 10 h, and treated according to the general preparation 2 to give compound (IV-7), 0.88 g (60.69%), mp 236-237° C., M+ 373.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([N:18]1[CH2:19][C:20]2[C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[C:21]=2[CH2:22][CH2:23]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Product: O=C(c1ccccc1)N1CCc2c(c(=O)[nH]c3ccccc23)C1

Procedure:
In the same way as described in example 2, the title product was prepared starting from phenylisocyanate and the pyrrolidine enamine of N-benzoyl-4-piperidone. Crystallization from methanol afforded analytical material, mp 275°-277° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[OH:22].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=1[OH:22])=[O:6]
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1F
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1F
Temperature: 80 °C
Yield: 48.9 %

Procedure:
A mixture of 0.49 g of 3-fluoroisonicotinic acid, 0.62 g of 2-amino-4-(trifluoromethyl)phenol, 1.00 g of WSC and 6 ml of pyridine was stirred while heating at 80° C. for two hours. The reaction mixture was cooled to room temperature, and then concentrated. Water was poured into the residue, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with a tert-butyl methyl ether-hexane mixture solvent to give 0.51 g of 3-fluoro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[N:9]([CH2:11][CH2:12][CH3:13])[CH:10]=1)=[O:5])C.C1COCC1.O.[OH-].[Li+].O>>[CH2:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[C:8]1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:31]([C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:30]=[N:29][N:28]=2)=[CH:19][CH:20]=1)[CH2:12][CH3:13]
Reactant: CCCn1cc(C(=O)OCC)nc1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCn1cc(C(=O)O)nc1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 40 h
Yield: 99.3 %

Procedure:
1-Propyl-2-[2′-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1H-imidazole-4-carboxylic acid ethyl ester (400 mg, 607 μmol) was dissolved in THF (12.0 mL, 148 mmol). A solution of lithium hydroxide monohydrate (127 mg, 3.0 mmol) in water (4.0 mL, 222 mmol) was then added and the mixture was stirred at 40° C. for 40 hours to yield the title compound (380 mg).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]([N:9]1[C:16](=[O:17])[CH2:15][C:13](=O)[NH:12][C:10]1=[O:11])([CH3:8])[CH3:7]>O>[CH:6]([N:9]1[C:16](=[O:17])[CH:15]=[C:13]([Cl:3])[NH:12][C:10]1=[O:11])([CH3:8])[CH3:7]
Reactant: CC(C)N1C(=O)CC(=O)NC1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)n1c(=O)cc(Cl)[nH]c1=O

Procedure:
350 ml of phosphorus oxychloride containing 15 ml of water are slowly run into 75 g (0.44 mole) of 1-isopropyl barbituric acid. After the violent exothermic reaction has abated, the reaction mixture is refluxed for 1 hour. The excess POCl3 is removed by evaporation in vacuo and the oily residue is poured onto ice, giving a precipitate which is filtered, washed with ice water and dried. 55 g of yellowish crystals are thus obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:10][C:9]1=[O:19])[CH2:2][CH2:3][CH3:4].[H][H]>C(O)C.[Pd]>[CH2:1]([O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:10][C:9]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCOCCn1cc(-c2ccccc2)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCCCOCCN1CC(c2ccccc2)NC1=O

Procedure:
A solution of 1-(2-butoxyethyl)-4-phenyl-4-imidazolin-2-one in ethanol with 10% palladium or carbon catalyst is reduced in an atmosphere of hydrogen. After the theoretical amount of hydrogen is absorbed, the catalyst is filtered and filtrate concentrated to give the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Fc1ccc(Cl)c(CBr)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cc(F)ccc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-5-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [O:1]=[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[H-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=O)[O:22]C1C=CC=CC=1.Cl>CN(C)P(=O)(N(C)C)N(C)C>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([CH:3]1[C:2](=[O:1])[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]1=2)=[O:22]
Reactant: O=C(Nc1ccccc1F)Oc1ccccc1
Reactant: O=C1Cc2ccccc2S1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(Nc1ccccc1F)C1C(=O)Sc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 50 g of 2,3-dihydro-2-oxo-benzo[b]thiophene in 200 ml of hexamethylphosphoric acid triamide is added dropwise to a suspension of 16 g of a 50% strength sodium hydride/mineral oil dispersion in 500 ml of hexamethylphosphoric acid triamide, whilst cooling, the temperature being kept below 15°. After stirring for one hour at room temperature, 77 g of phenyl N-(2-fluorophenyl)-carbamate are added in portions, with external cooling. The reaction mixture is stirred for a further 16 hours at room temperature and poured into a mixture of 300 ml of 2 N hydrochloric acid and 3,000 ml of ice water. An oil separates out and this crystallises after about 2 hours. The crystalline product, in which solvent is incorporated, is dissolved in 1,000 ml of diethyl ether and the solution is washed with water. The organic phase is separated off, dried over sodium sulphate and evaporated to dryness. The crude product is recrystallised from diethyl ether and gives N-(2-fluorophenyl)-2-oxo-2,3-dihydro-3-benzo[b]thiophenecarboxamide, melting point 155°-156°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[CH3:14])[CH3:2].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[Cl:16][S:17]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[C:8]([CH3:14])[C:9]=1[CH3:13])(=[O:19])=[O:18]
Reactant: CCOC(=O)COc1cccc(C)c1C
Reactant: O=S(=O)(O)Cl
Product: CCOC(=O)COc1ccc(S(=O)(=O)Cl)c(C)c1C
Temperature: 25 °C

Procedure:
Ethyl[(2,3-dimethylphenyl)oxy]acetate (6.1 g, 29.3 mmol) was added dropwise to chlorosulfonic acid (8.78 mL, 132 mmol) at 0° C., with stirring, causing a blood red solution. Reaction stirred for 30 minutes, then allowed to warm to RT. Mixture was stirred for a further 2 hours, then quenched by pouring over ice/water (200 mL). A dark red gum formed, this was extracted into dichloromethane (3×100 mL). Organics were concentrated in vacuo, to give a thick red oil, which crystallized on standing. Product was dried overnight in vacuum oven, to yield 8.179 g as red crystals. No further purification carried out. RT 1.25 mins.
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C([NH:27][OH:28])=O)(=O)=O)CC3)=NC=2)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH2:54][C@H:55]([CH:59]([CH3:61])[CH3:60])[C:56](O)=[O:57])(=[O:53])=[O:52])[CH2:47][CH2:46]3)=[N:43][CH:44]=2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[CH:41][C:42]([N:45]3[CH2:46][CH2:47][N:48]([S:51]([CH2:54][C@H:55]([CH:59]([CH3:61])[CH3:60])[C:56]([NH:27][OH:28])=[O:57])(=[O:53])=[O:52])[CH2:49][CH2:50]3)=[N:43][CH:44]=2)=[CH:37][CH:38]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)NO
Yield: 76 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methyl-butyramide, from 2-(R)-{4-[5-(4-chlorophenyl)pyridin-2-yl]piperazine-1-sulfonyl-methyl}-3-methylbutyric acid (0.068 g), to provide the title compound as a cream solid (0.053 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CCNCC3)cccc2n1
Yield: 96 %

Procedure:
1,1-dimethylethyl 4-(2-methyl-5-quinolinyl)-1-piperazinecarboxylate (D2) (1.1 g) in a 25% solution of trifluoroacetic acid in dichloromethane (10 mL) was stirred at r.t. under an inert atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure and desalted by means of a 20 g SCX cartridge affording the title compound in 96% yield (0.74 g).
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:11]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:12]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][C:32]([CH3:58])([O:34][C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][C@@H:42]([C:44]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:45])[NH2:43])=[O:36])[CH3:33].C(O)C.C([BH3-])#N.[Na+]>O1CCCC1>[C:1]([NH:9][C@@H:10]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:11]([S:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[CH2:12][NH:43][C@H:42]([C:44]([N:46]1[CH2:57][CH2:56][CH2:55][C@H:47]1[C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])=[O:45])[CH2:41][CH2:40][CH2:39][CH2:38][NH:37][C:35]([O:34][C:32]([CH3:58])([CH3:31])[CH3:33])=[O:36])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: COc1ccc(CS[C@H](C=O)C(Cc2ccccc2)NC(=O)c2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CSC(CN[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)[C@H](Cc2ccccc2)NC(=O)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
A mixture of (S)-β-(benzoylamino)-α-[[(4-methoxyphenyl)methyl]thio]-benzenebutanal (isomer A) (0.59 g. 1.40 mmole), 1-[N6 -[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester (1.55 g., 3.88 mmole), and crushed 3 A° molecular sieves (2.0 g.) in tetrahydrofuran (5 ml.) and absolute ethanol (5 ml.) is stirred at room temperature under argon. After stirring for 2 hours, sodium cyanoborohydride (0.27 g., 3 eq.) is added and stirring continued for 18 hours. The reaction mixture is filtered through Celite to remove the sieves. The filtrate is then diluted with ethyl acetate and washed with water, 1N hydrochloric acid (twice), 1N sodium bicarbonate, and brine. After drying over anhydrous MgSO4, the solvent is removed at reduced pressure to give the desired product, a mixture of diastereomers, as a pale yellow oil. TLC (silica gel, benzene:acetone 4:1) isomer A at Rf =0.31, and isomer B at Rf =0.15. Repeated chromatography (flash, silica gel LPS-1; chloroform:methanol, 98:2; hexane-acetone, 65:35; benzene:acetone, 4:1; ethyl acetate:hexane, 6:4; ethyl acetate:hexane, 6:4) gives 0.41 g. of 1-[N-[(3S)-3-(benzoylamino)-2-[[(4-methoxyphenyl)methyl]thio]-4-phenylbutyl]-N6 -[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester (isomer A) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.C(N(CC)CC)C.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>O1CCCC1>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3][N:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccnnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccnnc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 31 %

Procedure:
A stirred suspension of 2.6 grams (0.027 mole) of 4-aminopyridazine (prepared as in Example 1, Step A) in 100 ml of tetrahydrofuran is cooled to 0° C. and 4.6 ml (0.033 mole) of triethylamine is added in one portion. A solution of 4.1 ml (0.033 mole) of phenyl chloroformate in tetrahydrofuran is added dropwise during a 30 minute period. Upon completion of addition the reaction mixture is allowed to warm to ambient temperature where it is stirred for three days. The reaction mixture is concentrated under reduced pressure to a residue. The residue is taken up in 500 ml of chloroform and filtered to collect 1.9 grams of phenyl N-(4-pyridazinyl)carbamate; m.p. 184°-185° C. The filtrate is washed with water, then dried with magnesium sulfate. The mixture is filtered and the filtrate placed on a column of silica gel. Further elution is accomplished using 10% methanol in methylene chloride. The appropriate fractions are combined and concentrated under reduced pressure to yield an additional 1.8 grams of phenyl N-(4-pyridazinyl)carbamate. The nmr spectra are consistent with the proposed structure. The reaction is repeated several times.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)CNc1ccc(-c2ccc(F)cc2)nc1
Reactant: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1ccc(-c2ccc(F)cc2)nc1)N1CCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 98 mg (0.27 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt and 38.7 mg (0.54 mmol) pyrrolidine. Yield: 4 mg.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:26][CH:25]=1>>[CH3:23][C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:18]([C:12]3[S:13][C:14]4[CH2:15][CH2:16][O:17][C:8]5[CH:7]=[C:6]([C:4]6[CH:3]=[N:2][NH:1][CH:5]=6)[CH:22]=[CH:21][C:9]=5[C:10]=4[N:11]=3)=[O:20])[CH2:32][CH2:31]2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: Cc1cccc(N2CCNCC2)n1
Product: Cc1cccc(N2CCN(C(=O)c3nc4c(s3)CCOc3cc(-c5cn[nH]c5)ccc3-4)CC2)n1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(6-methylpyridin-2-yl)piperazine (1.2 equiv) to give 198 (M+1 473.0)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:36](=[O:37])[CH2:35][N:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: O=C(O)CN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)CN1CCOCC1)c1ccc(F)cc1
Yield: 9.3 %

Procedure:
A solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3, 0.16 g, 0.42 mmol), 2-morpholinoacetic acid (0.06 g, 0.42 mmol), HBTU (0.16 g, 0.42 mmol) and DIEA (0.16 g, 1.2 mmol) in DCM (3 ml) was stirred at room temperature for 1 hour. The reaction was then quenched with a saturated aqueous solution of NaHCO3, and extracted with DCM (2×50 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.02 g, 10%). 1H NMR (400 MHz, CD3OD) δ 7.35 (br s, 2H), 7.17 (br s, 1H), 7.01-6.97 (m, 2H), 6.06 (br s, 1H), 5.16-4.99 (m, 1H), 4.30 (br s, 2H), 3.68 (br s, 4H), 3.06 (br s, 2H), 2.48 (br s, 4H), 1.87-1.82 (m, 1H), 1.51 (d, J=6.4 Hz, 3H), 0.91 (br s, 2H), 0.64 (br s, 2H). MS: Calcd.: 511. Found: [M+H]+ 512.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][CH2:13][CH:14]([C:25]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:33](=[O:41])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)[NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][NH:20]2)(C)(C)C>ClCCl>[OH:12][CH2:13][CH:14]([C:25]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:33](=[O:41])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)[NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][NH:20]2
Reactant: CC(C)(C)OCC(Nc1ncnc2[nH]cnc12)c1nc2ccccc2c(=O)n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2ccccc2nc(C(CO)Nc2ncnc3[nH]cnc23)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 92 was prepared by adding trifluoroacetic acid to a solution of 2-[2-tert-butoxy-1-(9H-purin-6-ylamino)-ethyl]-3-phenyl-3H-quinazolin-4-one in dichloromethane. The reaction was stirred at ambient temperature for 18 hours, then concentrated in vacuo. Purification by LC provided the product as a white solid. MS (ES): m/z 400 (M+H), 382, 200, 136. Compound 92 is shown below.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][S:4][N:3]=1.C1(=O)[N:11](CCCBr)[C:10](=O)[C:9]2=CC=CC=[C:8]12>>[NH2:11][CH2:10][CH2:9][CH2:8][NH:1][C:2]1[N:6]=[CH:5][S:4][N:3]=1
Reactant: Nc1ncsn1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Product: NCCCNc1ncsn1

Procedure:
Reaction of 3-amino-1,2,4-thiadiazole with 3-phthalimidopropyl bromide and hydrazinolysis of the product gives 3-(3-aminopropylamino)-1,2,4-thiadiazole and from this intermediate N-cyano-N'-methyl-N"-[3-(3-(1,2,4-thiadiazolyl)amino)propyl]guanidine is prepared.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[C:35]1([CH2:41][CH2:42][C:43](Cl)=[O:44])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:43](=[O:44])[CH2:42][CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc(N2CCN(C(=O)CCc3ccccc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (80 mg, 0.22 mmol) in dichloromethane (4 ml) was added diisopropylethylamine (0.49 mmol, 81 μL) and 3-phenylpropionyl chloride (0.25 mmol). The reaction was stirred at room temperature for 16 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (43 mg) which was characterized by its mass spectrum: MS m/z (%): 491 ([M+H]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[CH:9](OC)OC)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:16]=[C:15]2[C:5](=[CH:4][CH:3]=1)[CH:6]=[N:7][C:8]([OH:14])=[CH:9]2
Reactant: COC(OC)C(=O)NCc1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc2cc(F)ccc2cn1
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
Into a RBF were added N-(4-Fluorobenzyl)-2,2-dimethoxyacetamide (1.53 g, 6.73 mmol) and sulfuric acid (18M; 3.4 mL, 61 mmol). This mixture was stirred at 85° C. for 5 min. Ice water was added and stirred; then solid NaHCO3 was added until the pH was 7-8. This was allowed to stir, then DCM was added and stirred to dissolve product. A solid precipitated out of the solution after 16 h. It was filtered off and dried in vacuo to give the title compound as yellow solid. HPLC: tR=2.07 min. (ZQ2, polar—5 min.). MS (ES+): m/z 164.24 (100) [MH+].