Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.[Br:12]N1C(=O)CCC1=O.BrBr>O>[Br:12][CH:10]([C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([Cl:8])[C:5]=1[F:9])[CH3:11]
Reactant: CCc1nc(Cl)nc(Cl)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Solvent: O
Product: CC(Br)c1nc(Cl)nc(Cl)c1F
Temperature: 82.5 °C
Reaction time: 2 h

Procedure:
A mixture of the compound of part (i) (400 g, N-bromosuccinimide (730 g), azoisobutyronitrile (33.7 g), bromine (65.5 g) and water (6.4 L) was heated at 80-85° C. for5 hours. Further N-bromosuccinimide (183 g) was added, heating continued for 2 hours then further azoisobutyronitrile (33.7 g) added. After heating for 2 hours at 85° C. further azoisobutyronitrile (33.7 g) was added and heating continued for 3 hours. The reaction was cooled, diluted with water (4 L) and extracted with dichloromethane (2×3 L). The combined organic extracts were washed with a solution of sodium metabisulphate (600 g) in water (2.5 L), followed by water (3 L). The solvent was removed by evaporation under reduced pressure, toluene (1.0 L) added and the solution concentrated under reduced pressure to give the product as an oil (534 g).
Reaction SMILES: C(O)=O.[C:4]1([C:13]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1.[C:22](=[O:29])([O:26]CC)[O:23][CH2:24][CH3:25].C[O-].[Na+].C(O)(=O)C>O>[C:22](=[O:26])([O:23][CH2:24][CH3:25])[O:29][C:4]1([CH:13]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)OCC
Reactant: C1=C(C2=CCCCCCCC2)CCCCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)OC1(C2CCCCCCCC2)CCCCCCCC1
Reaction time: 1.25 h

Procedure:
Into a 1 liter reaction vessel equipped with stirrer, thermometer and addition funnel are placed 339 grams (2.04 moles) of bicyclononenyl formate produced according to Example I containing compounds having the structures: ##STR175## 531 grams (4.5 moles) diethyl carbonate; and 31 grams (0.14 moles) of an aqueous 25% solution of sodium methoxide. The resulting mixture is stirred for a period of 1.25 hours. At the end of the 1.25 hour period, 30 grams (0.5 moles) of acetic acid and 2 liters of water is added to the reaction mass with stirring. The reaction mass is then washed with one 2 liter portion of saturated aqueous sodium chloride. The organic phase is then distilled on a 2" splash column yielding the following fractions:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].[CH3:27][Si:28]([CH2:31][CH2:32][O:33][CH2:34]Cl)([CH3:30])[CH3:29]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([CH2:34][O:33][CH2:32][CH2:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[N:3]=1.[N:19]1([C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:8]3[CH:7]=[N:6][C:5]4=[N:4][N:3]([CH2:34][O:33][CH2:32][CH2:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:2]=[C:10]4[CH:9]=3)[CH:12]=2)=[O:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(c1cccc(-c2cnc3[nH]nc(I)c3c2)c1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc2cc(-c3cccc(C(=O)N4CCOCC4)c3)cnc2n1
Product: C[Si](C)(C)CCOCn1nc(I)c2cc(-c3cccc(C(=O)N4CCOCC4)c3)cnc21
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
To a solution of [3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-5-yl)-phenyl]-morpholin-4-yl-methanone (2.12 g, 4.88 mmol) in anhydrous DMF (30 mL) was added sodium hydride (60% in mineral oil, 750 mg, 30 mmol) at 0-5° C. The mixture was stirred for a few minutes before trimethylsilylethoxymethyl chloride (2.0 ml, 11 mmol) was added drop wise at the same temperature. The mixture was stirred at 0° C. to room temperature for 4 hours and then cooled to 0-5° C. and quenched by an addition of methanol. The resulting suspension was then distributed between water, saturated aqueous ammonium chloride solution and ether. The aqueous phase was extracted three times with ether and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was then purified by silica gel chromatography using a gradient of ethyl acetate in hexanes to afford {3-[3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-morpholin-4-yl-methanone as a beige-brown foam (1.806 g, 66% by 1H-NMR, side product identified as morpholin-4-yl-{3-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-methanone). 1H-NMR (500 MHz, d6-DMSO) δ9.08 (d, 1H), 8.29 (d, 1H), 8.01 (m, 1H), 7.95 (t, br, 1H], 7.69 (t, 1H), 7.55 (d, br, 1H), 5.88 (s, 2H), 3.71 (t, 2H), 3.85-3.45 (m, 8H), 0.94 (t, 2H), −0.2 (s, 9H). MS: m/z 565 [MNa+], 537 [MH+], 447 [MH+-(Me3Si(CH2)2O)].
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:16][NH2:17])[CH2:5][CH2:4]1)=[O:2].[Cl:23][C:24]1[C:25](=[O:31])[NH:26][N:27]=[CH:28][C:29]=1Cl.C(N(CC)CC)C.C(O)CC>O>[Cl:23][C:24]1[C:25](=[O:31])[NH:26][N:27]=[CH:28][C:29]=1[NH:17][CH2:16][C:15]1[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:13]([O:12][CH2:11][CH2:10][CH2:9][N:6]2[CH2:5][CH2:4][N:3]([CH:1]=[O:2])[CH2:8][CH2:7]2)[CH:14]=1
Reactant: COc1ccc(CN)cc1OCCCN1CCN(C=O)CC1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Solvent: O
Solvent: CCCO
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cn[nH]c(=O)c2Cl)cc1OCCCN1CCN(C=O)CC1
Reaction time: 14 h
Yield: 47 %

Procedure:
A mixture comprising 11.58 g of 3-[3-(4-formylpiperazin-1-yl)-propoxy]-4-methoxybenzylamine, 5.0 g of 4,5-dichloro-3(2H)-pyridazinone, 4.6 g of triethylamine, 50 ml of n-propanol and 50 ml of water, was refluxed under heating with stirring for 14 hours. The solvent was distilled off under reduced pressure, and an aqueous potassium carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 6.21 g of the above-identified compound as slightly yellow white solid.
Reaction SMILES: O([C:8]([NH:10][C:11]1[S:15][N:14]=[N:13][CH:12]=1)=[O:9])C1C=CC=CC=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CC(C)=O>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:16][C:8]([NH:10][C:11]1[S:15][N:14]=[N:13][CH:12]=1)=[O:9]
Reactant: O=C(Nc1cnns1)Oc1ccccc1
Reactant: Nc1ccccn1
Solvent: CC(C)=O
Product: O=C(Nc1ccccn1)Nc1cnns1
Temperature: 25 °C

Procedure:
16.5 g (0.075 mol) 5-phenoxycarbonylamino-1,2,3-thiadiazole are suspended in 150 ml acetone and reacted with 9.4 g (0.1 mol) of 2-aminopyridine. The reaction mass is then refluxed for 3 hours. After cooling to room temperature the formed light brown crystals are removed by suction and dried. They are then recrystallized from ethanol. There is thus obtained the above noted title compound (compound No. 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:34][CH2:20][C:13]1[NH:12][C:11]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(c2cccnc2)=NC1c1ccc(F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2cccnc2)=NC1c1ccc(F)cc1Cl
Yield: 70.1 %

Procedure:
Ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-3-yl)-1,4-dihydropyrimidine-5-carboxylate (5 g, 13.4 mmol) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (4.25 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19](COC(=O)C(C)(C)C)[C:18](=[O:39])[N:17]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[NH:19][C:18](=[O:39])[N:17]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cn1c(=O)[nH]c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
4-[7-(2-Chlorophenyl)-1-(2,2-dimethylpropionyloxymethyl)-3-methoxycarbonylmethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (139 mg) was dissolved in tetrahydrofuran (1 ml) and methanol (1 ml), and sodium hydride (10 mg) was added to the solution. Then, the mixture was stirred at room temperature for 1 hour. The mixture was neutralized by adding 1N Hydrochloric acid, and was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation to give 100 mg of 4-[7-(2-chlorophenyl)-3-methoxycarbonylmethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. This compound was dissolved in N,N-dimethylformamide (2 ml) and potassium carbonate (20 mg) and methyl iodide (0.02 ml) were added to the solution. The mixture was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate, and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation to give 108 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:36])[C@H:24]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[NH2:25].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CO.C(N(CC)CC)C.CN(C)C=O>[CH3:21][O:22][C:23](=[O:36])[C@H:24]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[NH:25][C:17](=[O:19])[C@H:12]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Nα -Benzyloxycarbonyl-L-isoleucine, 2.65 g., and 2.54 g. of L-tryptophan methyl ester hydrochloride are dissolved in 30 ml. of dimethylformamide and cooled in an ice bath. Triethylamine, 1.4 ml., is added and then 1.5 g. of 1-hydroxy-benzotriazole. Lastly 2.3 g. of dicyclohexylcarbodiimide is added and the reaction let warm to room temperature with stirring continued for 40 hours. The mixture is filtered and the solvent evaporated. The residue is dissolved in 150 ml. of ethyl acetate and washed with 0.5 N hydrochloric acid, saturated sodium chloride solution, 5% sodium bicarbonate solution and finally with saturated sodium chloride solution. The ethyl acetate solution is dried over magnesium sulfate, filtered and the solution evaporated. The product is crystallized from methanol-ether-hexane to give 2.58 g. of the above named product, mp. 152°-155° C; [α]D23 -16.6° (c 1.95, methanol).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH2:9][CH2:10][OH:11])[CH:8]=1.FC(F)(F)C(O)=O.[CH2:20]([C:22]1[S:26][CH:25]=[C:24]([C:27]([N:29]2[CH2:34][C:33]3([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[O:32][CH2:31][CH2:30]2)=[O:28])[CH:23]=1)[CH3:21].C(N(CC)CC)C>C(#N)C>[CH2:20]([C:22]1[S:26][CH:25]=[C:24]([C:27]([N:29]2[CH2:34][C:33]3([CH2:39][CH2:38][N:37]([CH2:2][C:3]4[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH2:9][CH2:10][OH:11])[CH:8]=4)[CH2:36][CH2:35]3)[O:32][CH2:31][CH2:30]2)=[O:28])[CH:23]=1)[CH3:21]
Reactant: OCCc1cc(CBr)ccc1F
Reactant: CCc1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CCO)c4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
2-(5-(Bromomethyl)-2-fluorophenyl)ethanol (example 47, step a) (0.171 g) was added to a solution of (5-ethylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 99, step a) (0.3 g) and triethylamine (0.410 ml) in acetonitrile (15 mL) and the mixture stirred at 20° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 1% triethylamine and 2% methanol in dichloromethane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.2 g.
Reaction SMILES: F[C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:12][N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.C([OH:20])C>>[N+:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH+:12]([O-:20])[N:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1)([O-:10])=[O:9]
Reactant: Nn1cccc1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Reactant: CCO
Product: O=[N+]([O-])c1ccncc1[NH+]([O-])n1cccc1

Procedure:
A solution of 5 g of 3-fluoro-4-nitropyridine-N-oxide (disclosed in Talik and Talik, Roczniki Chemii, 38, 777 (1964)) and 5 g of 1-aminopyrrole in 75 ml of ethanol was stirred one hour at 85° C. and thereafter cooled and filtered to give 6 g of 4-nitro-N-(1H-pyrrol-1-yl)-3-pyridinamine-N-oxide as a solid, d 224°-226°. A 3 g sample was recrystallized from ethanol to give 2.2 g of crystals, d 224°-226°.
Reaction SMILES: BrC1N=C([C@@H]([NH:17][C:18](=[O:24])[O:19]C(C)(C)C)[C@H](O)C2C=CC=CC=2)C=CC=1.[Br:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH:33]=1)[CH:31]=O.C(OP([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=O)OCC)C>>[Br:25][C:26]1[CH:33]=[C:30]([C@@H:31]2[C@@H:42]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[O:24][C:18](=[O:19])[NH:17]2)[CH:29]=[N:28][CH:27]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cccc(Br)n1)[C@H](O)c1ccccc1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Product: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2ccccc2)O1

Procedure:
Prepared according to the same procedure as (±)-tert-Butyl (1R,2R)-1-(6-bromopyridin-2-yl)-2-hydroxy-2-phenylethylcarbamate, starting with 5-bromonicotinaldehyde and diethylbenzylphosphonate. 1H-NMR (CDCl3, 500 MHz) δ 8.67 (d, J=2.1 Hz, 1H), 8.37 (d, J=1.5 Hz, 1H), 7.91 (t, J=2.1 Hz, 1H), 7.43 (m, 3H), 7.30 (m, 2H), 7.12 (bs, 1H), 5.25 (d, J=7.6 Hz, 1H), 4.84 (d, J=7.6 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ ppm 159.0, 151.6, 146.4, 136.7, 136.4, 136.1, 129.7, 129.3, 126.1, 125.5, 121.6, 85.7, 62.3, 60.5. Mass spec.: 320.95 (MH)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl-].[F:11][C:12]1[CH:24]=[CH:23][C:15]([CH:16]=[N+:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=1.FC1C=CC(C=O)=CC=1.N1CCCCC1>>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:2]2[N:1]([CH2:6][CH2:7][CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(C=[N+]2CCCCC2)cc1
Reactant: OCCCn1cccc1
Agent: O=Cc1ccc(F)cc1
Agent: [Cl-]
Solvent: C1CCNCC1
Product: OCCCn1cccc1C(c1ccc(F)cc1)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 3-pyrrol-1-yl-propanol and 1-(4-fluorobenzylidene)-piperidinium chloride, which had been prepared in accordance with example 3 from 4-fluorobenzaldehyde and piperidine.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[NH2:10][C:11]1[NH:12][C:13]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17].N.CO>O1CCCC1>[NH2:5][C:3]([NH:10][C:11]1[NH:12][C:13]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[O:4]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: NC(=O)c1cc(-c2ccc3ccccc3c2)[nH]c1N
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)Nc1[nH]c(-c2ccc3ccccc3c2)cc1C(N)=O
Reaction time: 1.5 h
Yield: 58 %

Procedure:
Trichloroacetyl isocyanate (470 μL, 4.0 mmol) was added dropwise to a solution of 2-amino-5-(2-naphthyl)pyrrole-3-carboxamide (Reference compound No. 1-1, 1.0 g, 4.0 mmol) in anhydrous tetrahydrofuran (20 mL) at −30° C. over 5 minutes, and the whole was stirred for 1.5 hours. Furthermore, 2.0 M ammonia solution in methanol (20 mL, 40 mmol) was added thereto, and the whole was stirred at room temperature for 3 days. The precipitated solid was filtered off and washed with a mixed solvent of diethylether-ethanol (3:1) (20 mL). The obtained solid was dried at 40° C. under reduced pressure to give the target compound (0.67 g) as a pale gray solid (Yield 58%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH:16]([CH2:18][CH3:19])[CH3:17])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[SH:8].[CH:20](O)=O>>[CH:16]([NH:15][C:3]1[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([CH3:9])[N:6]=[C:7]2[S:8][CH:20]=[N:1][C:2]=12)([CH2:18][CH3:19])[CH3:17]
Reactant: O=CO
Reactant: CCOC(=O)c1c(C)nc(S)c(N)c1NC(C)CC
Product: CCOC(=O)c1c(C)nc2scnc2c1NC(C)CC

Procedure:
2.8 g. of 5-amino-4-sec.butylamino-6-mercapto-2-methylpyridine-3-carboxylic acid, ethyl ester are refluxed in 10 ml. of formic acid for 12 hours. After this time, the excess acid is removed in vacuo and the residue is dissolved in 10 ml. of water. The aqueous solution is made alkaline with sodium hydroxide and extracted twice, each time with 10 ml. of ether. The ether layer is collected, dried over calcium chloride and evaporated to dryness. The residue, 7-sec.butylamino-5-methylthiazolo[5,4-b]pyridine-6-carboxylic acid, ethyl ester is distilled in vacuo, b. p.0.01 180°-185°, yield 1.8 g. (62%).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]=[C:9]=[CH:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[C:14]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8]/[CH:9]=[CH:10]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCCCc1cccnc1
Reactant: O=C(O)C=C=C=C(c1ccccc1)c1ccccc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(/C=C/C=C(c1ccccc1)c1ccccc1)NCCCCc1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.4 %

Procedure:
To a stirred solution of 5,5-diphenyl-2,4-pentadienenoic acid (6.00 g) and triethylamine (3.7 mL) in dry tetrahydrofurane (40 mL) at 0°- C. was added a solution of ethyl chloroformate (2.37 mL) in tetrahydrofurane (15 mL) dropwise such that the reaction temperature was maintained at 0° C. After the addition was complete, the reaction was stirred at 0° C. for 15 minutes, then a solution of 3-pyridinebutanamine (3.78 g) in tetrahydrofurane (20 mL) was added dropwise while keeping the reaction at 0° C. The mixture was stirred at 0° C. for 1 hour and then at room temperature for 2 hours before the precipitated triethylamine hydrochloride was removed by filtration. The evaporated filtrate was partitioned between 1N hydrochloric acid solution (80 mL) and ether (80 mL). After the ethereal extract was discarded, the aqueous layer was basified with 4N sodium hydroxide (30 mL) and extracted with ether (4×100 mL). Evaporation of the dried (K2CO3) organic extracts afforded the crude amide which was purified by HPLC (hexane-ethyl acetate-triethylamine; 25:75:2) to provide 3.55 g of (E)-5,5-diphenyl-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide 0.2 molar hydrate as an oil.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:49])[CH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]([CH3:49])[CH:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C(=O)CCl)C1CCOCC1
Product: CCN(Cc1ccc(OCCN(C)C2CCOCC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 36.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-yl)acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.9 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH2:22][CH2:23][F:24].CC1C=CN=CC=1C1C=CC=C2C=1C=NN2>>[F:24][CH2:23][CH2:22][O:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: O=[N+]([O-])c1ccc(Br)c(OCCF)c1
Reactant: Cc1ccncc1B(O)O
Agent: Cc1ccncc1-c1cccc2[nH]ncc12
Product: Cc1ccncc1-c1ccc([N+](=O)[O-])cc1OCCF

Procedure:
Intermediate 16C was prepared from Intermediate 1A and Intermediate 16B by the procedure described for the preparation of Intermediate 1C, and was obtained as a beige solid (254 mg, 61% yield). MS (ES): m/z=277.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.CN(C)C=O.[NH2:22][C:23]([C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)([CH3:27])[C:24]([OH:26])=[O:25]>CCOCC>[NH2:22][C:23]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][CH:14]=[C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[C:8](=[O:12])[NH:7][C:6]2=[O:13])=[CH:32][CH:33]=1)([CH3:27])[C:24]([OH:26])=[O:25]
Reactant: CC(N)(C(=O)O)c1ccc(N)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(N)(C(=O)O)c1ccc(NC=C2C(=O)NC(=O)c3ccc(Br)cc32)cc1
Temperature: 110 °C
Yield: 33 %

Procedure:
A mixture of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (191 mg, 0.50 mmole), N,N-dimethylformamide (2 mL) and 2-Amino-2-(4-amino-phenyl)-propionic acid (90 mg, 0.50 mmole) is stirred and heated at 110° C. for one hour, cooled in the refrigerator. The reaction mixture is diluted with ether, filtered, washed with acetonitrile and dried to give a dull yellow solid 71 mg (33%), mp 250-253° C.; MS (ESI): m/z 428.2, 430.2 (M−H).