Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21](OCC)([O:25]CC)[O:22][CH2:23][CH3:24].C(O)(=O)C>O1CCCC1>[CH2:23]([O:22][C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:1][C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1)=[O:25])[CH3:24]
Reactant: CCOC(CCCCBr)(OCC)OCC
Reactant: Cc1cccc2cncn12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCc1cccc2cncn12
Reaction time: 0.29 h

Procedure:
5-Methylimidazo[1,5-a]pyridine [J. Org. Chem. 40, 1210 (1975), 424.7 g]is charged into a 12 liter flask equipped with mechanical stirrer, thermometer and nitrogen atmosphere. Dry tetrahydrofuran (THF, 3,000 ml) is charged into the flask and the resulting solution is cooled to -65° in a dry ice/acetone bath. n-Butyllithium (1.0 mole, 2.4 N in hexane) is poured into the flask all at once under a nitrogen atmosphere. The temperature rises to -32°. The mixture is recooled to -50° and a second mole of n-butyllithium is charged in the same manner. A second temperature rise occurs and after again cooling to -50°, a third mole of the n-butyl-lithium is charged into the reactor. The reaction mixture is then stirred for twenty minutes, the temperature drops to -65°. To this stirring solution a cold (-67°) solution of 5-bromo-1,1,1-triethoxypentane (606.9 g) in 500 ml of THF is added as rapidly as possible, raising the temperature to -25°. The reaction mixture is then warmed to -15° and stirred for 2 hours. Acetic acid (50 ml) is added and most of the solvent is removed under vacuum. The residue is taken up in 2,000 ml of ethyl ether; acetic acid (100 ml), and 12 N HCl (100 ml) are added while the reaction mixture is cooled to 0°. After 15 to 20 minutes, ice-cold 7.5 N ammonium hydroxide (1000 ml) is added. The organic phase is separated and the aqueous is washed again with ethyl ether (500 ml). The pH of the aqueous is adjusted to 9 with ammonium hydroxide and extracted again wth ethyl ether (500 ml). The combined ether extracts are washed with a dilute sodium chloride solution basified to pH 13-14 with potassium hydroxide. The ether extract is treated with charcoal and magnesium sulfate. The mixture is filtered and evaporated to give a dark oil which is dried at 2mm Hg. The oil is distilled under high vaccuum to give 5-(5-ethoxycarbonylpentyl)-imidazo[1,5-a]pyridine of Example 1, boiling at 220°/0.2 mm Hg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].[F:11][C:12]1[CH:20]=[CH:19][C:18](I)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:11][C:12]1[CH:20]=[CH:19][C:18]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: C#Cc1cncc(OC)c1
Reactant: O=C(O)c1cc(I)ccc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (70 mg, 0.10 mmol), copper (I) iodide (38 mg, 0.20 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (400 mg, 3.0 mmol) to a solution of 2-fluoro-5-iodobenzoic acid (0.53 g, 2.0 mmol) in triethylamine (4.2 mL, 30.0 mmol) and stir at room temperature for 1 h. Heat at 50° C. for 18 h. Cool to room temperature and concentrate. Purify by silica gel chromatography, eluting with 100:0 to 60:40 ethyl acetate:methanol. Triturate the resulting solid with 3:1 hexanes:methanol to give the title compound as an off-white solid (295 mg, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[CH:7]=O.[CH2:11]([NH2:13])[CH3:12].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[CH2:7][NH:13][CH2:11][CH3:12]
Reactant: O=Cc1cc(Br)ccc1I
Reactant: CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNCc1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-2-iodo-benzaldehyde (5.0 g, 16.1 mmol) in MeOH (20 mL) was added ethylamine (2M in MeOH; 16 mL, 24.0 mmol), followed by acetic acid (1.0 mL, 17.8 mmol), and the mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (2.0 g, 31.8 mmol) was then added over 5 minutes, and the reaction was stirred at room temperature over the weekend. The mixture was concentrated and partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@@H:17]([OH:19])[CH3:18])[CH2:8]1)[CH3:5])[CH3:2].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O>[C:35]([O:19][C@H:17]([C@@H:16]1[C@:20]2([CH3:28])[C@H:13]([C@H:12]3[C@H:23]([CH2:22][CH2:21]2)[C@:24]2([CH3:27])[C:9]([CH2:8][C@@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[CH2:26][CH2:25]2)=[CH:10][CH2:11]3)[CH2:14][CH2:15]1)[CH3:18])(=[O:37])[CH3:36]
Reactant: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)O)[C@@]4(C)CC[C@@H]32)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
iii)—A solution of (3β,20S)-3-[(1-ethoxyethyl)oxy]pregn-5-en-20-ol (56.9 g) in a mixture of dry pyridine (144 ml) and acetic anhydride (72.4 ml) was stirred at room temperature for 18 h. Water (482 ml) was added and stirring was continued for another 1 h. The product was extracted into ethyl acetate; the combined organic phases were washed with a saturated aqueous solution of sodium hydrogen carbonate and with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,20S)-3-[(1-ethoxyethyl)oxy]pregn-5-en-20-ol acetate (compound 4; 66.1 g) which was used in the following step without further purification.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9]O)=[O:8])=[CH:5][CH:4]=[C:3]([F:11])[CH:2]=1.CI.[H-].[Na+].CN(C)[CH:18]=[O:19]>>[CH3:9][C:7]([C:6]1[CH:5]=[CH:4][C:3]([F:11])=[CH:2][C:1]=1[O:19][CH3:18])=[O:8]
Reactant: O=C(CO)c1ccc(F)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1cc(F)ccc1C(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 13.9 g. of 2-hydroxy-4-fluoroacetophenone in 75 ml. of dry dimethylformamide were added 30 ml. of methyl iodide. The solution was cooled to 0° C. and 4.1 g. of a 50% oil dispersion of sodium hydride were carefully added. After stirring for one hour at 0° C., the reaction was extracted with ethyl acetate. The organic extract was washed three times with 200 ml. each of 1N hydrochloric acid. The ethyl acetate solution was then dried and removed in vacuo. This reaction and a subsequent identical reaction provided a total of 28 g. of 2-methoxy-4-fluoroacetophenone as an oil which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:23]([O:30][C@@H:31]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54][O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[O:34][C:32]1=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:23]([O:30][C@@H:31]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@@H:35]([CH2:54][O:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[O:34][C:32]1([C:15]1[S:14][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:17]=2[CH:16]=1)[OH:33])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(CCc2cccc3sccc23)cc1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cc3c(CCc4ccccc4)cccc3s2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a solution of 4-(2-phenylethyl)benzo[b]thiophene (0.4 g) in tetrahydrofuran (15 mL) was added n-butyllithium (2.44 mol/L n-hexane solution, 0.69 mL) at −78° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (0.82 g) in tetrahydrofuran (3 mL), and the mixture was stirred under ice-cooling for 10 minutes. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with diethylether. The extract washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give 2,3,4,6-tetra-O-benzyl-1-[4-(2-phenylethyl)benzo[b]-thiophene-2-yl]-D-glucopyranose (1.02 g). This material was dissolved in acetonitrile (13 mL) and triethylsilane (0.42 mL) was added to the solution. Boron trifluoride diethylether complex (0.18 mL) was added to the solution at −20° C., and the mixture was stirred at room temperature for 1 hour. A saturated potassium carbonate aqueous solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=8/1) to give the title compound (0.58 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O[C@@H:11]1[C@H:17]2[C@H:18]3[C@H:27]([CH2:28][CH2:29][C@:14]2([CH2:15][CH3:16])[C:13](=[O:31])[CH2:12]1)[C@@H:26]1[C:21](=[CH:22][C:23](=[O:30])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)(=O)C.O>CO>[CH3:16][CH2:15][C@:14]12[CH2:29][CH2:28][C@H:27]3[C@@H:18]([CH2:19][CH2:20][C:21]4[C@@H:26]3[CH2:25][CH2:24][C:23](=[O:30])[CH:22]=4)[C@@H:17]1[CH:11]=[CH:12][C:13]2=[O:31]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1C=CC2=O
Temperature: 40 °C
Yield: 68.7 %

Procedure:
Potassium carbonate (0.6 g, 4.4 mmol) was added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (3 g, 8.7 mmol) in methanol (27 ml) and the mixture was heated at 40° C. for 1 h. The mixture was allowed to cool to room temperature and water (100 ml) was then added. The precipitate was filtered, washed with water and dried under vacuum, to afford 18-methyl-estra-4,15-dien-3,17-dione (1.7 g, yield: 70%).
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2CCC[C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=CC=1.Cl.[C:15]1([C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[NH2:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:1].[C:15]1([C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[N:27]=[C:9]2[CH2:8][CH2:2][CH2:7][CH2:6][CH2:5][NH:13]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H]1CCCC[C@H]1c1ccccc1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Product: c1ccc([C@@H]2CCCC[C@H]2N=C2CCCCCN2)cc1

Procedure:
Following the procedure of Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride an appropriate amount of trans-2-phenylcyclohexylamine hydrochloride, M.P. 251°-257° C., and employing a reaction time of 38 days, the desired product was obtained, M.P. 236°-239° C.
Reaction SMILES: [C:1]1(=O)[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.C(O)(=O)C.[CH3:13][O:14][CH2:15][C:16]([NH2:22])=[CH:17][C:18]([O:20][CH3:21])=[O:19].S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(OCC)(=O)C>[OH:7][C:4]1[CH:3]=[C:2]2[C:1](=[CH:6][CH:5]=1)[NH:22][C:16]([CH2:15][O:14][CH3:13])=[C:17]2[C:18]([O:20][CH3:21])=[O:19]
Reactant: COCC(N)=CC(=O)OC
Reactant: O=C1C=CC(=O)C=C1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCc1[nH]c2ccc(O)cc2c1C(=O)OC
Yield: 44.6 %

Procedure:
32.4 g (300 mmol) of 1,4-benzoquinone was dissolved in 200 ml of ethyl acetate, 200 ml (350 mmol) of acetic acid was added thereto, followed by dropwise addition of 14.5 g (100 mmol) of methyl 4-methoxy-3-amino-2-butenoate. With stirring, the reaction mixture was heated for 15 hours while keeping the inner temperature at 50° C. To this was then added dropwise 200 ml of an aqueous solution containing 52.2 g (300 mmol) of sodium hydrosulfite. The mixture was further stirred at room temperature for 2 hours while controlling the reaction mixture within a pH range of from 4.5 to 7.5 with 5 N sodium hydroxide. Thereafter, crystals thus precipitated were collected by filtration and washed with ethyl acetate to obtain 7.33 g of crude crystals. The filtrate and the washings were combined and then allowed to separate into organic and water layers. The water layer was extracted with 50 ml of ethyl acetate, and the resulting ethyl acetate layer was combined with the organic layer. The thus combined organic layer was washed with saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was filtered off and the solvent was distilled off under reduced pressure, the resulting residue was purified by an alumina column chromatography (eluent: ethyl acetate). Main fractions thus obtained were concentrated, and the concentrated residue was slurried with 150 ml of ethyl acetate. The thus obtained crude product was combined with the crude crystals previously collected by filtration, and the combined product was recrystallized from 260 ml of ethyl acetate to obtain 10.5 g of the title compound with a yield of 44.2%.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]#[N:9])=[C:5]([NH2:7])[N:6]=1.CN(C)C=O.[SH2:15]>C(N(CC)CC)C>[CH3:1][C:2]1[S:3][C:4]([C:8](=[S:15])[NH2:9])=[C:5]([NH2:7])[N:6]=1
Reactant: Cc1nc(N)c(C#N)s1
Reactant: S
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)c(C(N)=S)s1
Yield: 58 %

Procedure:
5.5 parts of 2-methyl-4-amino-5-cyano-thiazole in 50 parts of dimethylformamide and 10 parts of triethylamine are reacted with 3 parts of hydrogen sulfide as described in Example 1(a). 4.0 parts of 2-methyl-4-amino-5-thiocarbamoylthiazole (58% of theory) of melting point 209°-213° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[OH-].[Na+].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>CO.O>[CH3:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:9])[CH:10]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc(C)cc1C
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)C=Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
2,4-Dimethylacetophenone (44ak, 1.48 g, 10.0 mmol) and sodium hydroxide (0.54 g, 13.5 mmol) were combined in methanol (30 ml) and stirred for 30 min at room temperature. A solution of benzaldehyde (1b, 1.02 ml, 10.0 mmol) and methanol (30 ml) was added dropwise and the mixture stirred for 18 hr at room temperature. Water (25 ml) was added and the mixture neutralized with hydrochloric acid (1 N). The mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford an oil. The crude oil was distilled bulb to bulb to give 1.98 g (84%) of a yellow oil: [expected mp 68° C.]; 1H NMR δ 2.37 (s, 3H), 2.44 (s, 3H), 7.05 (m, 2H), 7.16 (d, 1H, J=16.1 Hz), 7.38 (m, 3H), 7.49 (d, 1H, J=15.9 Hz), 7.54 (m, 3H); 13C NMR: δ 20.4, 21.4, 126.0, 126.6, 128.2, 128.5, 128.8, 130.4, 132.2, 134.7, 136.1, 137.4, 140.8, 145.0, 195.6.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][Mg]Br>C(OCC)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([CH3:15])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCOCC
Product: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
To a solution of 1-Boc-4-piperidone (10.0 g, 50.0 mmol) in diethyl ether (100 mL) at 0° C. was added methylmagnesium bromide (3.0 M in Et2O, 22.3 mL, 67.0 mmol) maintaining the temperature below +10° C. The reaction mixture was allowed to warm to RT over 1 h. The reaction was quenched by addition of sat. aq. NH4Cl solution, then the mixture was extracted with diethyl ether (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane, to give the title compound (6.76 g, 62%). 1H NMR (400 MHz, CDCl3): 1.26 (3H, s), 1.45 (9H, s), 1.48-1.62 (4H, m), 3.15-3.32 (2H, m), 3.70 (2H, d, J 12.5).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[I:1]
Reactant: CO
Reactant: COc1ccc(C(=O)O)c(I)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)cc1I

Procedure:
411 G. of 2-iodo-4-methoxy-benzoic acid, 4 l. methanol and 400 ml. of concentrated sulfuric acid are heated at reflux for 4 hours. The solution is then evaporated under reduced pressure, treated with water, and extracted with ether. The organic phase is then washed with aqueous sodium thiosulfate solution and aqueous sodium bicarbonate solution and subsequently dried over sodium sulfate. The solution is filtered, evaporated under reduced pressure and distilled. There is obtained the 2-iodo-4-methoxy-benzoic acid methyl ester, having a boiling point of 95°-98°/0.04 mm.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([OH:28])[CH:22]=3)=[N:19][N:20]=2)[C@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>N1C=CC=CC=1.C(Cl)Cl>[C:32]([O:28][C:23]1[CH:22]=[C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@H:13]([O:15][C:16](=[O:17])[CH2:12][CH2:13][CH3:14])[CH3:14])=[N:20][N:19]=2)[CH:26]=[CH:25][C:24]=1[F:27])(=[O:33])[CH2:31][CH2:30][CH3:29]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O)c3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Oc1cc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)OC(=O)CCC)o2)ccc1F
Reaction time: 23 h

Procedure:
To a solution of 2-chloro-4-((1R,2R)-1-(5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (Example 41) (135.5 mg, 0.34 mmol) in pyridine (0.6 mL) and CH2Cl2 (4 mL) was added n-butyryl chloride (0.17 mL, 1.68 mmol). Upon complete addition the reaction mixture was stirred for 23 h, then quenched with 10% aqueous HCl (6 mL). The mixture was partitioned between H2O (40 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (40 mL). The combined organic extracts were washed with NaHCO3 (45 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (20-25% EtOAc in hexanes) to provide the title compound as an off white solid (137.3 mg, 74%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 7.94 (ddd, J=2.2, 4.5, 8.6 Hz, 1H), 7.86 (dd, J=2.0, 7.0 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.8, 10.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.13 (d, J=8.8 Hz, 1H), 5.68 (pentet, J=6.5 Hz, 1H), 5.36 (dd, J=6.5, 8.4 Hz, 1H), 2.67 (t, J=7.2 Hz, 2H), 2.28-2.22 (m, 2H), 2.07-2.03 (m, 2H), 1.82-1.71 (m, 2H), 1.53 (d, J=6.5 Hz, 3H), 1.03 (t, J=7.2 Hz, 3H), 0.82 (t, J=7.4 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@H:8]1[C:12]2[NH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:11]=2[C:10](=[O:25])[NH:9]1.Br[C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]=[C:32]2[NH2:42]>O1CCOCC1.O>[NH2:42][C:32]1[C:31]2[C:36](=[C:27]([C:14]3[NH:13][C:12]4[C@@H:8]([CH3:7])[NH:9][C:10](=[O:25])[C:11]=4[CH:15]=3)[CH:28]=[CH:29][CH:30]=2)[N:35]=[C:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]=1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: CC(C)(C)Nc1nc(N)c2cccc(Br)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(N)nc(NC(C)(C)C)nc34)[nH]c21
Temperature: 80 °C
Yield: 49.6 %

Procedure:
Argon was bubbled into a slurry of potassium carbonate (Mallinkrodt; 0.140 g, 1.016 mmol), dichlorobis(p-dimethylaminophenylditbutylphosphine)palladium (ii) (Aldrich; 0.018 g, 0.025 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705; 0.133 g, 0.51 mmol), 8-bromo-N2-(tert-butyl)quinazoline-2,4-diamine (484b; 0.075 g, 0.254 mmol) in 2 mL dioxane and 0.4 mL water for 1 min. The reaction was sealed and heated to 80° C. for 30 min. The reaction was adsorbed onto 1 g silica gel and dried in vacuo. The material was treated with purified by silica gel chromatography (12 g column) using 0-100% (90/10 (DCM/2.0 M NH3/MeOH) in DCM). The product-containing fractions were concentrated to afford (R)-2-(4-amino-2-(tert-butylamino)quinazolin-8-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (0.044 g, 0.126 mmol, 49% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (1H, s), 7.97 (1H, dd, J=7.6, 1.2 Hz), 7.83 (1H, d, J=8.0 Hz), 7.59 (1H, s), 7.32-7.47 (2H, m), 7.02 (1H, t, J=7.7 Hz), 6.76 (1H, d, J=1.2 Hz), 6.47 (1H, br. s.), 4.56 (1H, q, J=6.7 Hz), 1.49 (9H, s), 1.41 (3H, d, J=6.7 Hz). m/z (ESI, +ve ion) 351.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31].C(=O)([O-])[O-].[K+].[K+].O>CC1CCCO1>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:35]2[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(N)=O)CCOCC1
Temperature: 78 °C
Reaction time: 10 h
Yield: 67.3 %

Procedure:
To a stirred solution of (S)-tert-butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (produced in step (i), 27 g) in 2-methyltetrahydrofuran (8 rel. vol.) was added 4-cyanophenyl boronic acid (1.1 mol. eq.), potassium carbonate (2 mol. eq.), water (2 rel. vol.) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.0065 mol. eq) at room temperature. Reaction mixture was heated to 78° C. and stirred for 10 h under nitrogen. The reaction mixture was cooled to room temperature and passed through a pad of celite. Water was added to the mixture and the layers separated. The organic layer was separated and concentrated to 5 rel. vol. under vacuum. The concentrated organic portion was stirred for 6 h at room temperature and the resulting solid filtered and washed with 2-methyltetrahydrofuran (2 rel. vol.). The solid was dried at 50° C. under vacuum to afford the sub-titled compound (17.3 g).