Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.OC1C=CC=CN=1.C[O:27][C:28]([C:30]1[N:31]([CH3:35])[CH:32]=[CH:33][N:34]=1)=O>COC(C1N(C)C=CN=1)=O>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][C:28]([C:30]3[N:31]([CH3:35])[CH:32]=[CH:33][N:34]=3)=[O:27])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: COC(=O)c1nccn1C
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Agent: Oc1ccccn1
Product: Cn1ccnc1C(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
A melt of 3-[2-(4-amino-1-piperidyl)ethyl]indole (1.0 g, 4.11 mmol), 2-hydroxypyridine (0.3 g, 3.16 mmol) and 2-methoxycarbonyl-1-methyl-1H-imidazole (0.57 g, 4.07 mmol) was heated at 160° C. for 3 hours under N2. More 2-methoxycarbonyl-1-methyl-1H-imidazole (5 drops) was added and heating continued for a further 11/2 hours. The mixture was cooled and chromatographed on silica (100-200 aktiv) eluting with absolute ethanol. The title compound was isolated as a brown glass (0.97 g,).
Reaction SMILES: N.CO.C([O:12][C@@H:13]1[C@@H:17]([CH2:18][O:19]C(=O)C2C=CC=CC=2)[S:16][C@@H:15]([N:28]2[CH:35]=[CH:34][C:32]([NH2:33])=[N:31][C:29]2=[O:30])[CH2:14]1)(=O)C1C=CC=CC=1>CO>[C@@H:15]1([N:28]2[CH:35]=[CH:34][C:32]([NH2:33])=[N:31][C:29]2=[O:30])[S:16][C@H:17]([CH2:18][OH:19])[C@@H:13]([OH:12])[CH2:14]1
Reactant: Nc1ccn([C@H]2C[C@H](OC(=O)c3ccccc3)[C@@H](COC(=O)c3ccccc3)S2)c(=O)n1
Agent: N
Solvent: CO
Product: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)S2)c(=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
1 mL of a 7 mol/L ammonia/methanol solution was added to a solution of 9.6 mg of 1-(2-deoxy-3,5-bis-O-benzoyl-4-thio-β-D-ribofuranosyl)cytosine in 1 mL of methanol, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, the solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/methanol=95/5 to 30/70), so as to obtain 4.7 mg of 1-(2-deoxy-4-thio-β-D-ribofuranosyl)cytosine in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([OH:10])[C:7]=1[CH:8]=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1.[OH-].[Na+]>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10][C:21]2[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: O=Cc1c(O)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2C=O)n1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
Under a nitrogen atmosphere a solution of 2.0 grams (0.013 mole) of 6-chlorosalicylaldehyde in 10 mL of dimethylformamide was stirred, and 1.94 grams (0.0141 mole) of potassium carbonate was added. The reaction mixture was then stirred for 10 minutes, and a solution of 2.6 grams (0.013 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine (prepared in Steps A-C) in 15 mL of dimethylformamide was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was warmed to 60° C. where it was stirred for 18 hours. The reaction mixture was poured into 150 mL of water, cooled, and the pH was adjusted to 12 with aqueous 50% sodium hydroxide, with stirring. The mixture was stirred for 15 minutes, and the resultant solid was collected by filtration to yield 1.62 grams of 6-chloro-2-(4,6-dimethoxypyrimidin-2-yloxy)benzaldehyde. The nmr spectrum was consistent with the proposed structure. The reaction was repeated several times.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.Br[C:15]1[CH:16]=[CH:17][C:18]2[N:24]([CH3:25])[CH2:23][CH2:22][C:21]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:36]([CH3:43])[CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:31][CH:30]=3)=[O:27])=[CH:20][C:19]=2[CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH3:25])[CH2:23][CH2:22][C:21]([C:26]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([CH2:35][N:36]([CH3:43])[CH:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:33][CH:34]=4)=[O:27])=[CH:20][C:19]=3[CH:44]=2)=[CH:4][CH:5]=1)[CH3:11]
Reactant: CCOc1ccc(OB([O-])[O-])cc1
Reactant: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C)cc1
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
In water:ethanol:toluene (1:1:10, 18.0 ml) were dissolved 4-ethoxyphenyl borate (252 mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepine-4-carboxamide (613 mg), and to the mixture was added potassium carbonate (420 mg). The mixture was stirred under argon atmosphere for 30 minutes, and to the mixture was added tetrakistriphenylphosphine palladium (59 mg). Under argon atmosphere, the mixture was refluxed for 17 hours. The mixture was diluted with ethyl acetate (200 ml) and washed with water (50 ml) and saturated brine (50 ml). The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (75 g, ethyl acetate:ethanol=9:1) and recrystallized from ethanol to give 7-(4-ethoxyphenyl)-1-methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepine-4-carboxamide (Compound 306) (230 mg, 35%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][C:39]([F:42])([F:41])[F:40])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23]CC4C=CC([N+]([O-])=O)=CC=4)=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]>CO.O1CCCC1.[C].[Pd]>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][C:39]([F:41])([F:42])[F:40])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=C(Cl)CS[C@H]23)cs1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=CNc1nc(C(=NOCC(F)(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=C(Cl)CS[C@H]23)cs1
Yield: 70.2 %

Procedure:
A suspension of 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 1.8 g.) and 10% palladium carbon (0.9 g.) in methanol (20 ml.) and tetrahydrofuran (20 ml.) was treated in a similar manner to that of Example 21-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2,2,2-trifluoroethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.0 g.).
Reaction SMILES: [Na].[C:2]([O:11]C)(=O)[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[SH:5].[C:13]1([NH:19][C:20](=[N:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[C:24]1([NH:23][C:20]([C:21]2[S:5][C:4]3[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=3[C:2]=2[OH:11])=[N:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCC(=Nc1ccccc1)Nc1ccccc1
Reactant: COC(=O)c1ccccc1S
Agent: [Na]
Solvent: CO
Product: Oc1c(C(=Nc2ccccc2)Nc2ccccc2)sc2ccccc12
Temperature: 0 °C
Yield: 76.9 %

Procedure:
A solution of 2.3 g (0.1 mol) of sodium in 150 ml of methanol is mixed with 16.8 g (0.1 mol) of methyl thiosalicylate and then a solution of 24.4 g (0.1 mol) of N,N'-diphenyl-2-chloro acetamidine in 250 ml of methanol is added. After heating under reflux for 1 hour, the mixture is poured into ice water and the precipitate filtered and recrystallized from an ethanol/water solution to yield 26.5 g of yellow needles having an m.p. of 152°-153° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([NH:10][C:11](=[O:22])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:21])[C@H:18]([CH3:20])[NH2:19])[CH3:9].O1CCOCC1.CN(C)C=O>CO>[CH2:8]([NH:10][C:11](=[O:22])[C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:21])[C@H:18]([CH3:20])[NH:19][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH3:9]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1COCCO1
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)CCC(=O)O

Procedure:
500 mg of succinic anhydride was added to a solution of 500 mg of alanyl proline ethylamide in form of dioxane (10 ml) and 0.25 ml of dimethylformamide and the reaction solution heated under reflux for 30 minutes. Then the solution was evaporated and the residue crystallized from 10 ml of acetone and 30 ml of ether. 510 mg of a product having a melting point of 139 to 141 degrees C. was obtained. [α[D20 -129.2 degrees (c 0.3; 50% methyl alcohol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]=[C:16]3[O:21][C:20](=[O:22])[CH2:19][O:18][C:17]3([CH3:24])[CH3:23])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C-]#N.[K+]>C(#N)C.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]3[C:20](=[O:22])[CH2:19][O:18][C:17]([CH3:23])([CH3:24])[C:16]3=[O:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1C=C1OC(=O)COC1(C)C
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)COC(C)(C)C1=O
Yield: 89.9 %

Procedure:
To a suspension of 6-[1-(4′-chloro-4-methylbiphenyl-3-yl)methylidene]-5,5-dimethyl-[1,4]dioxan-2-one (1.5 g, 4.38 mmol) in anhydrous acetonitrile (22 ml) is added triethylamine (0.67 ml, 4.81 mmol) and potassium cyanide (30 mg, 0.46 mmol). The reaction mixture is stirred under reflux for two hours. The cooled mixture is diluted with ethyl acetate, and 0.5N aqueous hydrochloric acid is added at 0° C. The organic layer is separated and the aqueous phase extracted twice with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is purified by flash chromatography (heptane/ethyl acetate 1:1 ratio) to afford 4-(4′-chloro-4-methylbiphenyl-3-yl)-2,2-dimethylpyran-3,5-dione (1.35 g) as a foam. A sample of the product is stirred in hexane/diisopropyl ether (4:1 ratio) and filtered to give a white solid with a melting point of 186-188° C.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([NH:13][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: Nc1ccccc1
Product: CCCCCCC/C=C/C(=O)Nc1ccccc1

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and aniline as starting materials to give the aimed compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][C:10]=2[CH2:9]1)(OC(C)(C)C)=O.[ClH:23]>CCOC(C)=O>[ClH:23].[C:17]1([C:15]2[S:14][C:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]=3[CH:16]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(-c3ccccc3)cc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(-c2cc3c(s2)CCNC3)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from Step 2 was dissolved in EtOAc at -25° C. and treated with HCl gas until saturated. The reaction was stoppered and stirred at 0° C. for 1 h. Removal of the solvent in vacuo afforded the title compound as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH2:14][CH2:15][CH3:16])[N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH:3]=1>C(O)C.[Pd]>[CH2:14]([N:8]([N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[C:4]1[CH:3]=[CH:2][N:7]=[CH:6][N:5]=1)[CH2:15][CH3:16]
Reactant: CCCN(c1cc(Cl)ncn1)n1cccc1
Agent: [Pd]
Solvent: CCO
Product: CCCN(c1ccncn1)n1cccc1
Yield: 117.5 %

Procedure:
To a slurry of 10% Pd/C (1.0 g) and MgO (0.8 g) in 10 ml ethanol (100%) was added 6-chloro-N-propyl-N-(1H-pyrrol-1-y)-4-pyrimidinamine (4.9 g), in 90 ml ethanol (100%) and the mixture was hydrogenated under atmospheric pressure at room temperature for 6 hours. The mixture was filtered and the filtrate evaporated to yield 4.92 g of a solid which was eluted with 10% ethyl acetate/DCM on a silica gel column via flash method. The desired fractions were evaporated to yield 2.45 g (57.8%) of an oil, N-propyl-N-(1H-pyrrol-1-yl)-4-pyrimidinamine.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16](O)=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].C[N:21]1CCOCC1.ClC(OCC)=O>O1CCCC1.C(Cl)Cl>[C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([NH2:21])=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2]
Reactant: CN1CCOCC1
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(N)=O)NC1=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (0.30 g, 1.05 mmol) is dissolved in tetrahydrofuran (5.0 mL). 4-Methylmorpholine (0.14 mL, 1.05 mmol) is then added, and the reaction is cooled to -20° C. Ethyl chloroformate (0.1 mL, 1.05 mmol) is then added, and the reaction is stirred at -20° C. for 30 minutes. The reaction is then filtered, and the filtrate is concentrated to give a yellow oil. This oil is dissolved in methylene chloride (20.0 mL), and anhydrous ammonia gas is bubbled through the solution for 1 hour. The bubbling is stopped, and the reaction is stirred an additional 1 hour. The solvent is evaporated, and the residue is partitioned between ethyl acetate and water. The aqueous layer is extracted several times with ethyl acetate, the combined organic layers are dried (Na2SO4), and the solvent is evaporated to give trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxamide, MS: M+1=287.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14].C(O)C>C(O)(=O)C>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC(C)=O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 60 °C
Yield: 89.5 %

Procedure:
A solution of 6.3 g. of acetonine in a mixed solvent comprising 20 g. of acetone and 2 g. of ethanol was added with 0.5 g. of acetic acid. The mixture was heated at 60°C. for 10 hours in a sealed equipment to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 89.5%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-])=O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>CO.CN(C=O)C.[Pd]>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([NH:11][C:14](=[O:16])[CH3:15])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)Nc1cc(C(C)=O)ccc1O

Procedure:
A solution of 1-(4-hydroxy-3-nitro-phenyl)-ethanone (10 g) in methanol, DMF (50 ml) and acetic anhydride (10 ml) was hydrogenated using 10% Pd—C (0.45 g) for 2 h at 30 psi. The catalyst was filtered off. The filtrate was concentrated (5 ml) and treated with EtOAc (100 ml) to obtain the title compound, which was filtered, washed with EtOAc (10 ml) and dried. Yield, 9.1 g (85%); mp, >215° C.; MS (EI): 193 (M+), 151, 136, 108.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1>CO.O>[NH2:11][C:10]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1cnc(N)c([N+](=O)[O-])c1
Solvent: O
Solvent: CO
Product: NC(=O)c1cnc(N)c(N)c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
44.5 g of 6-amino-5-nitro-nicotinamide (0.24 mol; HPLC: 93% area) were suspended in methanol/water 1:1 (500 mL), 5.0 g of catalyst [Pd(4%)-Ru(1%)/C paste (62% H2O type: 485; Johnson Matthey); type: 485; Johnson Matthey] was added. Hydrogenation was carried out at 5 bar and 30° C. for 5 h. After completion the catalyst was filtered off and washed with methanol/water 1/1 (50 mL). 480 mL of the solvent was distilled off. The resulting suspension was cooled to 20° C. and filtered off. The solid was washed with methanol (20 mL) and TBME (30 mL). After drying (200-10 mbar; 40° C. bath temperature, 16 h) 27.3 g of the title compound (0.18 mol, 73%) were obtained.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13]Br)=[O:6])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[SH:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>CC(C)=O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:25]2[CH:26]=[CH:27][C:22]([SH:21])=[CH:23][CH:24]=2)=[CH:24][CH:23]=1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CBr
Reactant: Sc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CSc1ccc(Sc2ccc(S)cc2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
trans-2-Bromomethyl-cyclohexanecarboxylic acid cyanomethylamide (259 mg) and cesium carbonate (340 mg) were weighed into a 15 mL vial fitted with a stir bar and a vent cap. Acetone (3 mL) and 4-mercaptothiophenol (256 mg) were added. The reaction mixture was stirred at 50° C. overnight and then diluted with hot acetone (7 mL) and filtered through Celite™. The Celite™ was washed with hot acetone (25 mL). The filtrate and wash were combined and the solvent was removed on a rotary evaporator. Chromatography of the crude product on C-18 reverse-phase HPLC provided the title compound as a cream solid. 1H NMR (DMSO-d6): δ=8.65 (1H, t), 7.46 (2H, dd), 7.27 (4H, d), 7.21 (2H, dd), 4.12 (2H, d), 3.50 (1H, br m), 2.98 (1H, d), 2.6 (1H, m), 2.1 (2H, m), 1.7 (4H, m), 1.1 (4H, m).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([C:43]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:41][CH:42]=1>>[C:46]([NH:45][C:43]([C:40]1[N:39]=[CH:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:42][N:41]=1)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)NC(=O)c1ncc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnc(C(=O)NC(C)(C)C)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-one and 5-bromo-N-tert-butylpyrimidine-2-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.287 min, m/z=531.3; 1H NMR (CDCl3) 1.11 (s, 3H), 1.18 (s, 3H), 1.49 (s, 9H), 1.54 (m, 3H), 2.04 (s, 1H), 2.11 (m, 2H), 2.21 (m, 2H), 2.34 (m, 1H), 2.78 (m, 1H), 5.67 (m, 1H), 7.06 (m, 2H), 7.19 (m, 1H), 7.25 (m, 6H), 7.84 (s, 1H), 8.85 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CC(C)=O>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[S:24][C:25]=3[CH3:26])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1sc(-c2ccccc2)nc1CBr
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 1 a], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 4-bromomethyl-5-methyl-2-phenyl-thiazole [PCT Int. Appl. (2001), WO 0119805 A1] in the presence of cesium carbonate and potassium iodide in acetone for 14 h at ambient temperature to give the title compound as yellow oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[CH:5]1[CH2:16][C:15]2[CH:14]=[C:13]3[C:9]([CH:10]=[CH:11][NH:12]3)=[CH:8][C:7]=2[CH2:6]1)[CH2:2][CH3:3].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:16][C:15]2[CH:14]=[C:13]3[C:9]([C:10]([CH:29]=[O:30])=[CH:11][NH:12]3)=[CH:8][C:7]=2[CH2:6]1)[CH2:18][CH3:19]
Reactant: CN(C)C=O
Reactant: CCCN(CCC)C1Cc2cc3cc[nH]c3cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCCN(CCC)C1Cc2cc3[nH]cc(C=O)c3cc2C1
Temperature: 50 °C
Yield: 30 %

Procedure:
A solution of dipropyl-(1,5,6,7-tetrahydro-1-aza-s-indacen-6-yl)amine (100 mg, 0.39 mmol) in dimethyl formamide (5 mL) was added to a solution of phosphorous oxychloride (200 μL, 329 mg, 2.14 mmol) in dimethyl formamide (5 mL) at -5° C. The mixture was heated at 50° C for 2 hours, poured on ice and treated with 5M sodium hydroxide and heated again for 20 minutes. After cooling, the mixture was extracted using dichloromethane. The combined organic extracts were dried (magnesium sulfate), filtered and evaporated to yield a residue of 70 mg, which was purified on silica using methanol as eluant, yielding 33 mg (30%) of the pure compound as an oil.:
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][NH:15][CH3:16]>C1COCC1>[CH3:14][N:15]([CH3:16])[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CNC
Reactant: O=Cc1ccc(C(F)(F)F)nc1Cl
Solvent: C1CCOC1
Product: CN(C)c1nc(C(F)(F)F)ccc1C=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
To a stirred solution of 2-chloro-6-(trifluoromethyl)nicotinaldehyde (115 mg, 0.549 mmol) in THF (1 mL) was added dimethylamine (823 μl, 1.65 mmol). The reaction was heated to 50° C. and stirred for 3 hours. The reaction was loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to yield the desired compound (50 mg, 0.229 mmol, 41.8% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[CH2:10][CH2:11]Cl)=[CH:4][C:3]=1[Cl:14].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[Cl:14])[NH:8][C:9](=[O:13])[CH2:10][CH2:11]2
Reactant: O=C(CCCl)Nc1ccc(Br)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2cc(Br)c(Cl)cc2N1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A flame-dried 50-mL flask equipped with a magnetic stirring bar was charged with N-(4-bromo-3-chloro-phenyl)-3-chloro-propionamide (1.0 g, 3.36 mmol) and aluminium chloride (0.67 g, 5.04 mmol). In a pre-heated oil bath, the flask was heated at 135˜140° C. for 2 hr. After cooling to room temperature, the reaction mixture was treated with ice-water slowly, and extracted with EtOAc. The organic layer was washed with water and brine in sequence, dried over anhy. Na2SO4. After evaporation of the solvent, the residue was purified by recrystallization in EtOAc (2 mL) and gave title compound (0.44 g, 50% yield) as a solid. MS: 260.0 (M+H)+.