Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]([C:9](=[O:11])[CH3:10])=[CH:6][O:7][CH3:8])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:4][C:5]([C:9](=[O:11])[CH2:10][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:6][O:7][CH3:8])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC=C(OC(C)=O)C(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC=C(OC(C)=O)C(=O)CC(=O)c1ccccc1
Temperature: -78 °C

Procedure:
To a solution of 545 mg (3.5 mmol) of 1-methoxy-3-oxobut-1-en-2-yl acetate in THF (14.2 mL) at −78° C. was added LHMDS (3.45 mL of a 1 M solution in toluene) dropwise. After stirring for min at −78° C., the reaction mixture was treated with 0.4 mL (3.5 mmol) of benzoyl chloride dropwise, then removed from the cold bath and allowed to warm to room temperature and continue stirring for 18 h. The reaction was quenched with 10 mL 10% aq HCl and extracted with diethyl ether (3×10 mL). The organic fractions were combined, washed with sat. aq. NaCl, dried (Na2SO4), and concentrated under reduced pressure to provide 1-methoxy-3,5-dioxo-5-phenylpent-1-en-2-yl acetate which was used the subsequent step without further purification. To a solution of crude 1-methoxy-3,5-dioxo-5-phenylpent-1-en-2-yl acetate (3.5 mmol) in toluene (35 mL) was added pyridinium p-toluenesulfonate (130 mg, 0.5 mmol). The reaction mixture was heated at reflux under a nitrogen atmosphere for 1 h before being cooled and concentrated under reduced pressure and purified by flash chromatography (80 g SiO2, 0-100% ethyl acetate/hexanes gradient elution) to provide 4-oxo-6-phenyl-4H-pyran-3-yl acetate. LC/MS (M+H)+ 231.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:17]([CH3:18])=[C:16]([Cl:19])[N:15]=[C:14](Cl)[C:13]1=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][NH2:29])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:23]1([CH3:22])[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][NH:29][C:14]2[C:13](=[O:21])[N:12]([CH2:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C:17]([CH3:18])=[C:16]([Cl:19])[N:15]=2)=[CH:25][CH:24]=1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: Cc1ccc(CCN)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(CCNc2nc(Cl)c(C)n(CC(=O)OCc3ccccc3)c2=O)cc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A solution of 1-benzyloxycarbonylmethyl-3,5-dichloro-6-methylpyrazinone (656 mg, 2.00 mmol), as prepared in the preceding step, 4-methylphenethylamine (380 mg, 2.81 mmol), triethylamine (405 mg, 4.01 mmol), and ethyl acetate (20 mL) was refluxed overnight. After cooling to room temperature, the solution was washed with 10% citric acid (×2). The aqueous solutions were back extracted with dichloromethane. The combined organic layers were dried (Na2SO4) and contracted to give the title compound as a yellow solid (854 mg, 100%). 1H NMR (CDCl3) δ 7.38-7.32 (m, 5H), 7.12 (s, 4H), 6.09 (s, 1H), 5.21 (s, 2H), 4.79 (s, 2H), 3.65 (dd, 2H, J=7.0, 13.0 Hz), 2.88 (t, 2H, J=7.1 Hz), 2.32 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:19]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][Br:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc(Br)ccc1OCc1ccccc1
Solvent: CCOCC
Product: BrCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A solution of 2-benzyloxy-5-bromobenzyl alcohol (14.75 g, 50.2 mmol) in anhydrous ethyl ether (150 ml) was cooled to 4° C. A solution of PBr3 (13.68 g, 50 mmol) in anhydrous ether (40 ml) was added dropwise keeping the temperature below 10° C. The reaction was allowed to warm to ambient temperature and stirred for 1 hour. The reaction was filtered through silica gel (200 g). The silica gel was washed with ethyl ether to remove all the product. The filtrate was washed with water (1×150 ml), aqueous saturated sodium hydrogen carbonate (1×150 ml) and brine (1×150 ml). The organic layer was dried (Na2 SO4) and evaporated to give 2-benzyloxy-5-bromobenzylbromide as a pale yellow oil (15.2 g, 85%) which crystallised on standing.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH:13][CH3:14])[CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:13]([CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)[CH3:14])=[O:19]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CNCCC#Cc1cccc(CF)n1
Product: CN(CCC#Cc1cccc(CF)n1)C(=O)c1ccccc1Cl
Yield: 31.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from 4-(6-(fluoromethyl)pyridin-2-yl)-N-methylbut-3-yn-1-amine (70 mg, 0.36 mmol) and 2-chlorobenzoyl chloride (76 mg, 0.44 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 37 mg of 2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-N-methylbenzamide as a brown oil (Yield: 31%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].Br[C:13]#[N:14]>C(O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:13]([NH2:14])=[N:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: N#CBr
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: CCO
Solvent: O
Product: Nc1nc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C

Procedure:
7.6 g (50 mmol) of 4-nitro-ortho-phenylenediamine was dissolved were dissolved in 100 mL of ethanol and 20 mL of H2O. 7.9 g (75 mmol) of BrCN was added in one portion to this stirring solution, and the resulting mixture was heated under reflux for 1.0 h. The reaction mixture was cooled to room temperature, concentrated to 20 mL then neutralized with saturated NaHCO3 solution to pH 8, and resulting solid 5-nitro-1H-benzoimidazol-2-ylamine collected via filtration was used directly in the next step without further purification.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][CH:10]1[C:40]1[C:45]2[CH2:46][CH2:47][O:48][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([CH2:57][CH3:58])=[CH:53][CH:52]=2)[CH:41]=1)C1C=CC=CC=1>C1COCC1.CO.[Pd]>[CH2:57]([C:54]1[CH:53]=[CH:52][C:51]([CH2:50][C:42]2[CH:41]=[C:40]([C@H:10]3[C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3)[C:45]3[CH2:46][CH2:47][O:48][C:44]=3[C:43]=2[Cl:49])=[CH:56][CH:55]=1)[CH3:58]
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)OCC3)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A suspension of compound 72 (490 mg, 0.61 mmol) and Pd/C (10% wt., 74 mg) in THF (4 mL) and MeOH (2 mL) was stirred at room temperature under an atmosphere of H2 for 14 hours. The mixture was filtered through a Celite pad and concentrated in vacuo. The residue was purified by prep HPLC (C18) to afford the product E020 (25 mg, 8%) as a brown solid.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)[C:2]([NH2:4])=[O:3].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=O)[NH:19][CH:20]=1.N1CCCCC1>C(O)C>[NH:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[CH:21][C:18]1[NH:19][CH:20]=[C:16]([Br:15])[CH:17]=1)[C:2]([NH2:4])=[O:3]
Reactant: O=Cc1cc(Br)c[nH]1
Reactant: NC(=O)Nc1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)Nc1ccc2c(c1)C(=Cc1cc(Br)c[nH]1)C(=O)N2

Procedure:
To a solution 5-ureidoindolin-2-one (326 mg, 1.71 mmol) in ethanol was added 4-bromo-2-pyrrolecarboxaldehyde (297 mg, 1.71 mmol), and piperidine (0.2 mL). The reaction mixture was refluxed for 18 hours. The mixture was cooled and filtered to afford a golden-colored solid which was washed with ethanol and ether to afford 5-ureido-3-[(4-bromopyrrol-2-yl)methylene]indolin-2-one; (453 mg); 1H NMR (400 MHz, DMSO-d6) δ 5.77 (s, 2H); 6.74–6.76 (d, 1H); 6.96 (s, 1H); 7.02–7.04 (dd, 1H); 7.41–7.42 (m, 1H); 7.52–7.53 (m, 1H); 7.73–7.74 (d, 1H); 8.34 (s, 1H); 10.82 (bd, 1H); 13.5 (bs, 1H) ppm.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([Cl:30])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13](C2C=CC(C(OC(C)(C)C)=O)=CC=2N)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](O)([C:33](F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([Cl:30])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:33]2[CH:31]=[CH:5][C:1]([NH2:6])=[CH:2][CH:3]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)c(N)c1
Solvent: ClCCl
Product: Nc1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
Cyclopentyl-[2-(4-BOC-aminophenyl)-5-chloro-1H-indol-7-yl]-amine (430 mg, 1 mmol) prepared in Example 78 was added to DCM (5 mL). TFA (5 mL) was added thereto, and the mixture was stirred for 2 h. After completion of the reaction, TFA was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (310 mg, Yield 95%).
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[C:7](=[O:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2]
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1(C)CC(O)C(C)C(C)(CC)N1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
19.7 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidone were dissolved in 250 ml of methanol, and 3.7 g of sodium borohydride were added thereto in four portions over a period of 1 hour, with stirring. After stirring the mixture for a further 4 hours, it was allowed to stand overnight and was then concentrated by evaporation under reduced pressure; water was added to the concentrated mixture, which was then extracted with benzene. The resulting benzene solution was dried over potassium carbonate and the benzene was distilled off. The residue was distilled under reduced pressure, giving 17.2 g of the title compound as a colourless liquid (bp 125° - 129° C/1.5 mmHg).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:18]([F:19])=[CH:17][C:13]([C:14](N)=[O:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-:30].[K+]>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:18]([F:19])=[CH:17][C:13]([C:14]([OH:15])=[O:30])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C(N)=O)c1ccc(F)cc1
Agent: [K+]
Solvent: CCO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C(=O)O)c1ccc(F)cc1
Temperature: 95 °C

Procedure:
(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinamide (Example 2; 1.0 g, 2.5 mmol) was dissolved in a 10% aqueous EtOH solution (10 ml) at 25° C., followed by addition of solid KOH (2.8 g, 50.0 mmol). The reaction solution was heated to 95° C. for 4 days, cooled to 25° C., and extracted with DCM (2×50 ml). The aqueous layer was then acidified to pH 3. The resulting solid (0.55 g), was collected by filtration and dried under vacuum to give the title compound. MS: Calcd.: 399. Found: [M+H]+ 400.
Reaction SMILES: [SH:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[C:3]([OH:5])=[O:4].N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CCOCC>[CH2:28]([O:27][C:25]([S:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[C:3]([OH:5])=[O:4])=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc2cc(C(S)C(=O)O)ccc2c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)SC(C(=O)O)c1ccc2cc(OC)ccc2c1
Reaction time: 2 h

Procedure:
A solution of α-mercapto-6-methoxy-2-naphthylacetic acid (0.02 moles) in 25 ml. of pyridine is cooled in an ice bath. To this is added dropwise 2.1 mol (0.022 moles) of ethyl chloroformate. The mixture is then stirred for 2 hours, diluted with ether and filtered. The mixture is basified with 10% sodium bicarbonate solution. The alkaline mixture is worked with ether, then acidified with 10% hydrochloric acid, washed with ether, dried and filtered. The solvent is removed and the residue is triturated with hexane to obtain α-ethoxycarbonylthio-6-methoxy-2-naphthylacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][S:24]([CH3:23])(=[O:26])=[O:25])[CH:15]=3)[C:11]([O:21][CH3:22])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(O)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cnc(-c2ccc(F)cc2)nc1-c1cccc(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
1.2 g of 2-(4-fluorophenyl)-4-(3-hydroxyphenyl)-5-methoxypyrimidine and 0.57 g of methanesulfonyl chloride were added to 10 ml of pyridine, and the resulting mixture was stirred for 3 hours at room temperature. After completion of the reaction, ice-cold water was added to the mixture. Subsequently, the mixture was extracted with ethyl acetate. The solvent was evaporated off, and the residue was purified by column chromatography on silica gel, thereby obtaining 1.0 g 2-(4-fluorophenyl)-4-(3-methanesulfonyloxyphenyl)-5-methoxypyrimidine (Compound 54).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:3]([O:4][CH3:5])[CH3:2])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A 1-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and an addition funnel was charged with N,O-dimethylhydroxylamine hydrochloride (20 g, 0.20 mol) and CH2Cl2 (250 mL). The mixture was cooled to 0° C. and triethylamine (24 g, 0.20 mol) was added, followed by a solution of 4-chlorobenzoyl chloride (35.8 g, 0.2 mol) in CH2Cl2 (100 mL). After the addition was complete, the cooling bath was removed, and the reaction was allowed to warm to rt and was stirred overnight. The reaction mixture was quenched with satd. aq. NH4Cl (200 mL). The mixture was transferred to a separatory funnel, the layers were separated and the aqueous layer was extracted with CH2Cl2 (200 mL). The combined organic layers were washed with aq. NaHCO3, brine, and then dried over anhydrous MgSO4. After filtration, the solvents were evaporated under reduced pressure to afford the benzamide (37 g, 92%) as a colorless oil. IR (film): 2935, 1639, 1593, 1460, 1415, 1212, 1090, 1015, 887, 838, 747, 730 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.58 (d, J=8.6 Hz, 2H), 7.32 (d, J=8.6 Hz, 2H), 3.55 (s, 3H), 3.11 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.2, 137.3, 132.9, 130.5, 128.8, 61.7, 34.1. HRMS (EI): m/z calcd for C9H11ClNO2 [M+H]+, 200.0478; found, 200.0484.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])([O-:25])=[O:24]
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2ccccc12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Ethyl 2-aminobenzo[b]thiophene-3-carboxylate (5 g) and 2-fluoro-nitrobenzene (2 ml) were dissolved in N,N-dimethylformamide (150 ml) and heated to 60° C. Thereto was added potassium carbonate (8 g) and the mixture was stirred at 100° C. for 18 hr. After cooling, the reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration. The crystals were washed with water and diisopropyl ether and dried at 60° C. to give ethyl 2-(2-nitroanilino)-benzo[b]thiophene-3-carboxylate (5.7 g).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C:5]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:34]1([NH:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>[Cu]>[C:34]1([N:40]([C:41]2[CH:42]=[C:43]([CH3:47])[CH:44]=[CH:45][CH:46]=2)[C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([N:40]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:41]5[CH:42]=[C:43]([CH3:47])[CH:44]=[CH:45][CH:46]=5)=[CH:9][CH:10]=4)[C:5]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:4]=3[CH:3]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cc1cccc(Nc2ccccc2)c1
Reactant: COC(=O)CCC1(CCC(=O)OC)c2cc(I)ccc2-c2ccc(I)cc21
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CCC1(CCC(=O)OC)c2cc(N(c3ccccc3)c3cccc(C)c3)ccc2-c2ccc(N(c3ccccc3)c3cccc(C)c3)cc21
Temperature: 150 °C

Procedure:
A mixture of 17.0 grams of 2,7-diiodo-9,9-bis[2-(methoxycarbonyl)ethyl]fluorene, 4.3 grams of copper bronze, 12.5 grams of potassium carbonate in 30 milliliters of Soltrol 220 was mechanically stirred and heated to 150° C. under a nitrogen atmosphere. Fifteen (15.0) grams of molten N-phenyl-m-toluidine was added dropwise at this temperature. After addition, the resulting mixture was heated at 210° C. under reflux for 24 hours. The hot reaction mixture was filtered, and the filter cake was washed several times with hot cyclohexane. The combined filtrate was evaporated under reduced pressure to give a brown residue which was purified by column chromatography on silica gel to afford 15.2 grams of pure 2,7-bis(phenyl-m-tolylamino)-9,9-bis[2-(methoxycarbonyl)ethyl]-fluorene, melting point 159° to 160° C.
Reaction SMILES: [N:1]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[N+]=[N-].C(N(CC)CC)C.Br.[Br:19][CH2:20][CH2:21]N>C(Cl)Cl>[C:4]([NH:1][CH2:21][CH2:20][Br:19])([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: NCCBr
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCBr
Reaction time: 3 h

Procedure:
A mixture of t-butyl azidoformate (15.81 g) and triethylamine (30 ml) was added dropwise to a stirred suspension of 2-bromoethylamine hydrobromide (20.5 g.), in methylene chloride (100 ml.). The mixture was stirred for 3 hr., then filtered. The filtrate was concentrated to a small volume, and the residue was distributed between ether and water. The ether layer was dried, then distilled under reduced pressure, collecting the fraction b.p. 92°-94°/0.9 mm as N-carbo-t-butoxy-2-bromoethylamine (1.756 g.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@H:4]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[NH:5][C:6](=[O:33])[C@H:7]([CH:30]([CH3:32])[CH3:31])[NH:8][C:9](=[O:29])[C@H:10]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:28])[NH2:27])[N:11](C(OC(C)(C)C)=O)[N+:12]([O-:14])=[O:13].[ClH:43]>C(O)(=O)C.O1CCOCC1>[ClH:43].[CH3:1][O:2][C:3](=[O:42])[C@H:4]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[NH:5][C:6](=[O:33])[C@H:7]([CH:30]([CH3:32])[CH3:31])[NH:8][C:9](=[O:29])[C@H:10]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[NH:27])[NH2:28])[NH:11][N+:12]([O-:14])=[O:13]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N(C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N[N+](=O)[O-])C(C)C
Reaction time: 0.08 h

Procedure:
30.9 g of t-butoxycarbonylnitroarginylvalyltyrosine methyl ester is dissolved in 177 ml of acetic acid. To this solution is added 88.5 ml of 6 N hydrochloric acid in dioxane. The reaction is allowed to stand for five minutes and the solvent is removed under vacuum. The residue is triturated with ethyl ether. The resultant precipitate is filtered, washed with ethyl ether and dried in a vacuum oven at 55° C. to afford nitroarginylvalyltyrosine methyl ester hydrochloride.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7](I)[N:6]=[C:5]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:3][CH2:2]1.[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1>>[CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:37]3[CH:38]=[N:33][CH:34]=[N:35][CH:36]=3)[N:6]=[C:5]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1c(I)nc(-c2cccc(C(F)(F)F)c2)n1C1CC1)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cncnc1
Product: O=C(c1c(-c2cncnc2)nc(-c2cccc(C(F)(F)F)c2)n1C1CC1)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [3-cyclopropyl-5-iodo-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 63) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as yellow amorphous solid. MS: 511.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4](Cl)[N:3]=1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4]([N:20]2[CH2:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: C1CNC1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nc(N2CCC2)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1

Procedure:
(+)-(1S,2R,4R)-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)cyclopentanol (340 mg, 1.20 mmol) and azetidine (98%, Aldrich, 1.0 mL) and methanol (6 mL) were maintained at 60° C. in a sealed tube for 18 hours. To the cooled solution was added 1N sodium hydroxide (1.2 mL). Volatiles were evaporated and the residue chromatographed on silica gel. Title compound was eluted with methanol:ethyl acetate/15:85 as a white foam which solidified to white powder from methanol-acetonitrile (333 mg, 91%), mp 194-195°; mass spectrum (Cl, CH4) 305 (M+1); 1H-NMR (DMSO-d6)δ: 7.81 (s, 1, H8), 5.88 (br s, 2, NH2), 495-4.80 (m, 1, CH--N), 4.76 (d, J=3.9 Hz, 1, OH), 4.66 (t, J=5.0 Hz, 1, CH2 --OH), 4.4-4.15(br m, 4, 2CH2N), 4.10-4.0 (m, 1, CHO), 3.6-3.4 (m, 2, CH2O), 2.5-1.9 (m, 6, methylene), 1.75-1.5((m, 1, 1/2CH2); [α]20589 +10.1°, [α]20578 +10.7°, [α]20540 +11.9°, [α]20436 +18.3°, [α]20365 +25.2° (c=0.812, methanol).