Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].CN(C)C=O.[CH3:19][Si:20]([CH3:27])([CH3:26])[CH2:21][CH2:22][O:23][CH2:24]Cl>O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:27])([CH3:26])[CH3:19])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(Cl)nc21
Reaction time: 0.25 h

Procedure:
5 g of 2,6-dichloropurine was added to the mixture of 1.54 g of sodium hydride and 100 mL of N,N-dimethylformamide in an ice bath, and stirred at the same temperature for 15 minutes. 6.81 mL of 2-(trimethylsilyl)ethoxymethyl chloride was added to the reaction mixture, and was stirred at the same temperature for 5 hours. The reaction mixture was added with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in the subsequent order, and then dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography, to obtain 6.18 g of 2,6-dichloro-9-{[2-(trimethylsilyl)ethoxy]methyl}-9H-purine [56-1] as a light brown oily product.
Reaction SMILES: C(#N)C.C[O:5][C:6]1[CH:15]=[CH:14][C:13]([O:16]C)=[C:12]2[C:7]=1[N:8]=[CH:9][CH:10]=[N:11]2>[Ag].O>[N:8]1[C:7]2[C:6](=[O:5])[CH:15]=[CH:14][C:13](=[O:16])[C:12]=2[N:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(OC)c2nccnc12
Agent: [Ag]
Solvent: O
Solvent: CC#N
Product: O=C1C=CC(=O)c2nccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 22 g. of the silver catalyst prepared above, 148 ml. of acetonitrile, and 32 ml. of water was added over a 30 minute period to 2.0 g. of 5,8-dimethoxyquinoxaline. The reaction was stirred for two hours at room temperature. The catalyst was filtered off and washed with methylene chloride. Water was added to the filtrate and the filtrate was then extracted with the methylene chloride used to wash the catalyst. The methylene chloride was dried over sodium sulfate and evaporated to give the title compound as a brown powder which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:8]1[S:9][C:10]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cccc(Cl)c2s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc2nc(CBr)sc12
Temperature: 25 °C
Yield: 6.2 %

Procedure:
A mixture of 900 mg (4.9 mmol) of 7-chloro-2-methyl-1,3-benzothiazole (16-4), 1.13 g (6.37 mmol) of N-bromosuccinimide and 47 mg (0.196 mmol) of benzoyl peroxide in CCl4 (25mL) was refluxed under irradiation by a UV lamp for 4 hours. After this time the reaction was cooled to room temperature and the insolubles were filtered off. The reaction was purified on a silica column eluted with EtOAc:hexanes (3:97 to 1:1) and 80 mg of the desired product 16-5 was isolated. HRMS: measured 261.9080; theoretical 261.9087. 1H NMR (CDCl3): 4.80 (s, 2H), 7.43 (m, 2H), 7.92 (d, 1H).
Reaction SMILES: CN(C)CCNC.[Li]CCCC.[Cl:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([CH:22]=[O:23])=[CH:16][CH:15]=1.[I:24]I>COCCOC>[Cl:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([CH:22]=[O:23])=[C:16]([I:24])[CH:15]=1
Reactant: COc1nc(Cl)ccc1C=O
Reactant: II
Agent: CNCCN(C)C
Agent: [Li]CCCC
Solvent: COCCOC
Product: COc1nc(Cl)cc(I)c1C=O
Temperature: -23 °C
Reaction time: 0.33 h
Yield: 51.3 %

Procedure:
To a solution of N,N,N'-trimethylethylenediamine (2.46 mL, 19.23 mmol) in 15 mL of 1,2-dimethoxyethane at -23° C. was added n-BuLi (9.22 mL, 19.23 mmol), and the solution was stirred at -23° C. for 20 min. The mixture was transferred using a double-tipped needle to a solution of 6-chloro-2-methoxy-3-pyridinecarboxaldehyde (3.0 g, 17.5 mmol) in 40 mL of 1,2-dimethoxyethane at -23° C. After stirring for 15 min, n-BuLi (12.6 mL, 26.2 mmol) was added and the dark mixture was stirred an additional 2 h at -23° C. The solution was transferred using a double-tipped needle to a solution of iodine (8.04 g, 31.7 mmol) in 40 mL of 1,2-dimethoxyethane at -78° C. After stirring at -78° C. for 30 min, the cooling bath was removed and the reaction mixture was allowed to warm for 20 min, then quenched with water. The mixture was extracted with ether (2×30 mL) and the combined organic layers were washed successively with 30-mL portions of 10% aqueous Na2S2O3, water and brine, and dried over MgSO4. Concentration afforded 4.62 g (89%) of crude product to which was added 50 mL of hexanes. The mixture was stirred and allowed to stand at 5° C. overnight. Filtration gave 2.67 g of 6-chloro-4-iodo-2-methoxy-3-pyridinecarboxaldehyde as a yellow solid: mp 120°-124° C. Concentration of the hexane washings and purification of the residue by radial preparative thin-layer chromatography (silica gel, 5% ethyl acetate/hexanes) gave an additional 1.41 g of product (mg 120°-124° C.), raising the total yield of the compound to 78%. Recrystallization from hexanes gave an analytical sample as a bright yellow solid: mp 129°-130° C. 1H NMR (300 MHz, CDCl3) δ 10.16 (s, 1H), 7.59 (s, 1H), 4.07 (s, 1H); IR (nujol) 1690, 1350, 1260, 1095, 1010, 900, 840 cm-1.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].O.[CH2:8]=[CH:9][CH:10]=[CH2:11]>CCCCCCCC.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[CH2:2]([O:1][CH:8]=[CH:9][CH:10]=[CH:11][CH2:8][CH2:9][CH2:10][CH3:11])[CH:3]([CH2:5][OH:6])[OH:4]
Reactant: OCC(O)CO
Reactant: C=CC=C
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: O
Solvent: CCCCCCCC
Product: CCCCC=CC=COCC(O)CO
Temperature: 80 °C
Yield: 69.6 %

Procedure:
In a 500-mL autoclave, charged were 70 g (0.76 mol) of glycerin, 0.7 g (2.3 mmol) of bis(acetylacetonato)palladium (II), 2.7 g (5.0 mmol) of triphenylphosphine-2,2′-disulfonic acid dipotassium salt dihydrate and 35 g of water. The mixture was heated to 80° C., whereby a water-soluble liquid phase was obtained. After cooling, a hydrocarbon solvent phase containing 100 g (1.85 mol) of 1,3-butadiene dissolved in 100 g of n-octane was introduced at a time into the autoclave. While stirring, the mixture was heated to 80° C. again. The initial pressure in the autoclave showed 0.9 Mpa. After stirring at 80° C. for 12 hours, the water phase and unreacted butadiene were removed. The residue was washed with water and n-octane was removed, whereby 106 g of octadienyl glyceryl ether was obtained as a pale yellow transparent oil.
Reaction SMILES: [C:1]([O-])(=[O:5])[CH:2]([CH3:4])[OH:3].[Na+].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.Cl.[NH:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>CN(C)C=O>[OH:3][C@@H:2]([CH3:4])[C:1]([N:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])=[O:5]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(O)C(=O)[O-]
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of sodium lactate (1.7 g., 15.0 mmole), diphenylphosphorylazide (3.6 ml., 1.1 eq.), and dry dimethylformamide (30 ml.) at 0° (ice-bath) in an argon atmosphere is treated with triethylamine (2.1 ml., 1.0 eq.) and L-proline, phenylmethyl ester, monohydrochloride salt (3.6 g., 15.0 mmole). After 24 hours, the reaction mixture is partitioned between ethyl acetate and water. The aqueous phase is back extracted, the organic extracts are combined, washed with 5% potassium bisulfate, brine, and evaporated. The residue (5 g.) is chromatographed on silica (130 g.) eluting with (1:1, ethyl acetate/hexane) to give 2.5 g. of 1-[(S)-2-hydroxy-1-oxopropyl]-L-proline, phenylmethyl ester as a white crystalline solid after evaporation; m.p. 86°-88° (isopropyl ether). TLC (silica gel; ethyl acetate) Rf =0.4.
Reaction SMILES: [OH:1][CH:2]([C@H:6]1[O:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:8][C@H:7]1[CH2:16][O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])CCO.I([O-])(=O)(=O)=O>CC(C)=O.O>[CH:2]([C@H:6]1[O:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:8][C@H:7]1[CH2:16][O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:1]
Reactant: CC(C)(C)OC(=O)COC[C@@H]1OC2(CCCCC2)O[C@@H]1C(O)CCO
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COC[C@@H]1OC2(CCCCC2)O[C@@H]1C=O
Reaction time: 4 h
Yield: 92.2 %

Procedure:
A solution of 1,1-dimethylethyl [[(2S,3R) 3-(1,3-dihydroxypropyl)-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]acetate (50 g, 138 mmol) in acetone (350 mL) was treated with a solution of periodate (50 g, 235 mmol, 1.7 eq) in water (1.2 L). The reaction mixture was stirred vigorously under nitrogen and monitored by TLC. After about 4 hours, the reaction was complete by TLC analysis. Acetone was removed under reduced pressure without heating. The reaction mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were dried and concentrated under reduced pressure without heating to give 40 g of 1,1-dimethylethyl [[(2S,3S) 3-formyl-1,4-dioxaspiro[4,5]dec-2-yl]methoxy]acetate as a clear oil: [α]D=−1.142 (10.147 mg/cc in MeOH); 1H NMR (CDCl3) δ1.38 (m, 2H), 1.42 (s, 9H), 1.61 (m, 8H), 1.73 (m, 2H), 3.52 (dd, 1 H), 3.72 (dd, 1 H), 3.88 (s, 2H), 4.38 (dd, 1 H), 4.52 (m, 1H), 9.62 (s, 1H) ppm.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:75][CH:76]5[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]5)=[O:28])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
To a suspension of 0.0226 g (0.00005 mole) of 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-56a) in 3 mL of dimethylformamide was added 0.0121 g (0.00009 mole) of 1-hydroxybenzotriazole, 0.0312 g (0.00008 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate and 0.06 mL (0.00035 mole) of ethyldiisopropylamine. The mixture was stirred for 15 minutes and then 0.0091 g (0.00008 mole) of 4-amino-1-methylpiperidine was added. The mixture was stirred for an additional 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol 98:2-85:15) to give 0.0140 g of 4-(9-Cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-N-(1-methyl-piperidin-4-yl)-benzamide (I-56).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.N1C=CC=CC=1.[C:64](Cl)(=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>ClCCl>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][C:64](=[O:71])[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)c4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the Fr-900506 substance (9.7 mg) in dichloromethane (0.2 ml) and pyridine (0.1 ml) was added benzoyl chloride (50 μl) at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent was removed from the reaction mixture under reduced pressure to give a crude oil. This oil was purified on silica gel thin layer chromastography (developing solvent: diethyl ether and hexane, 2:1 v/v) to afford 17-allyl-12-[2-(4-benzoyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (8.0 mg).
Reaction SMILES: Cl.N[OH:3].[C:4]1([C:10]2[O:14][C:13]([CH:15]=[N:16]N3CC(=O)NC3=O)=[N:12][CH:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C>C(O)(=O)C>[C:4]1([C:10]2[O:14][C:13]([CH:15]=[N:16][OH:3])=[N:12][CH:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CN(N=Cc2ncc(-c3ccccc3)o2)C(=O)N1
Reactant: NO
Agent: C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: ON=Cc1ncc(-c2ccccc2)o1

Procedure:
Hydroxylamine hydrochloride (54 g, 0.78 mole) and 1-[[[5-phenyl-2-oxazolyl]methylene]amino]-2,4-imidazolidinedione (105 g, 0.39 mole) were refluxed with stirring in a solution of water (100 ml) and glacial acetic acid (1.0 l.) for five hrs. An additional 54 g of hydroxylamine hydrochloride was added while the mixture was refluxed another five hrs. The hot solution was treated with Darco, filtered and poured into water (5.0 l.). The solid was again refluxed in a mixture of hydroxylamine hydrochloride (50 g), acetic anhydride (800 ml) and water (80 ml) for four hrs. The solution was cooled, poured into water (3.0 l.) and the resulting solid was collected and dried (48 g, 65%). Recrystallization of a sample from acetonitrile gave product of analytical purity, m.p. 208°-210°.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].F[C:8]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:9]=1[CH:10]=O.Cl.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][NH2:26])[CH:20]=1>CN1CCCC1=O>[I:16][C:13]1[CH:12]=[C:9]2[C:8](=[CH:15][CH:14]=1)[N:25]([C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)[N:26]=[CH:10]2
Reactant: NNc1cccnc1
Reactant: O=Cc1cc(I)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Ic1ccc2c(cnn2-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Cesiumcarbonate (26.84 g, 82.38 mmol) is added to a suspension of 2-fluoro-5-iodobenzaldehyde (6.87 g, 27.46 mmol) and 3-pyridylhydrazine dihydrochloride (5 g, 27.46 mmol) in 136 mL N-methylpyrrolidon. The reaction mixture is stirred overnight at r.t. After checking that the hydrazone has been formed (1H-NMR) the reaction mixture is heated for 4 h at 160° C. The reaction mixture is allowed to cool down and the dark brown suspension is poured on 1000 mL ice water. After vigorously stirring at r.t. for 45 min, the precipitated product is sucked off via a glass microfibre filter, washed with water and dried at the evaporator at 45° C. 8.28 g (93.9%) of the title compound are obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccccc2C)c(C)c1
Temperature: 120 °C
Yield: 96 %

Procedure:
To a solution of methyl 4-bromo-3-methylbenzoate (ABCR, 15.0 g, 65 mmol) in toluene (200 mL) and water (200 mL), was added o-tolylboronic acid (10.7 g, 78 mmol) followed by potassium carbonate (45.3 g, 32.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.78 g, 3.3 mmol). The mixture was degassed with N2 and refluxed at 120° C. for 6 hours. After the completion of reaction, the reaction mixture was cooled to RT. The organic phase was separated and evaporated under reduced pressure. The crude compound was passed through a silica column using hexane as eluent to get the title compound as a white solid (15 g, 95%). 1H NMR (DMSO-d6, 400 MHz) δ 7.91 (s, 1H), 7.82 (m, 1H), 7.32 (m, 2H), 7.27 (m, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 3.84 (s, 3H), 2.09 (s, 3H), 1.95 (s, 3H). HPLC (Method B), Rt 3.01 min (purity: 98.71%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=2[O:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:3][CH2:2]1.O[CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([O:12][CH2:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[O:11])=[CH:8][C:7]=2[O:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Oc1cc(C(=O)O)ccc1OCC1CC1
Reactant: O=C(CO)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)Oc1cc(C(=O)OCC(=O)OCc2ccccc2)ccc1OCC1CC1
Yield: 52.3 %

Procedure:
A solution of 4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoic acid (0.300 g, 1.048 mmol), benzyl 2-hydroxyacetate (0.174 g, 1.048 mmol), EDC (0.603 g, 3.14 mmol), and DMAP (0.128 g, 1.048 mmol) in DCM (25 ml) was stirred at RT for 2 hours. The mixture was diluted with DCM and washed with HCl 1N and NaHCO35%. The organic phase was dried over Na2SO4, the solvent was removed under vacuum, and the crude was purified by flash chromatography on silica gel cartridge (petroleum ether:EtOAc=80:20 to 75:25). A further purification by trituration with EtOH was required to obtain 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoate (0.238 g, 0.548 mmol, 52.3% yield, MS/ESI+ 434.9 [MH]+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCOC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.005 mL (0.053 mMol) ethyl chloroformate, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [N:1]#N.[C:3]([OH:9])([C:5]([F:8])([F:7])[F:6])=[O:4]>C(Cl)Cl>[C:3]([OH:9])([C:5]([F:8])([F:7])[F:6])=[O:4].[C:3](#[N:1])[CH3:5].[C:3]([OH:9])([C:5]([F:8])([F:7])[F:6])=[O:4]
Reactant: N#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To N2 (0.033 g, 0.058 mmol) in DCM (0.20 mL) was added TFA (0.067 mL, 0.86 mmol). The reaction was stirred for 1 h at room temperature and then concentrated in vacuo. The residue was Purified by reverse phase chromatography: 5% (2 column volumes), 5-100% (10 column volumes) 0.1% TFA/acetonitrile//0.1% TFA/water) to provide Example 16 as a TFA salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][C@H:20]3[CH2:24][N:23]([C:25](=[O:43])[C@@H:26]([NH:34][C:35]([O:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[C@H:22]([C:44]([O:46]C)=[O:45])[CH2:21]3)=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[CH:48]=[CH2:49].[Li+].[OH-].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][C@H:20]3[CH2:24][N:23]([C:25](=[O:43])[C@@H:26]([NH:34][C:35]([O:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[C@H:22]([C:44]([OH:46])=[O:45])[CH2:21]3)=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[CH:48]=[CH2:49]
Reactant: C=CCCCCC[C@H](NC(=O)OCCCC=C)C(=O)N1C[C@H](Oc2cc(-c3ccccc3)nc3cc(OC)c(C=C)cc23)C[C@H]1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCCCCC[C@H](NC(=O)OCCCC=C)C(=O)N1C[C@H](Oc2cc(-c3ccccc3)nc3cc(OC)c(C=C)cc23)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A mixture of the product from Step 1 (0.68 g, 1.02 mmol) in THF (7 mL), MeOH (1 mL) and 1 M aqueous LiOH (7.15 mL, 7.15 mmol) was stirred at RT for 2 hours. The reaction mixture was acidified to pH 5 with 1 M aqueous HCl and extracted with EtOAc (3×70 mL). The combined organic phases were washed with water (50 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated to give the title compound (0.56 g). LRMS (ESI) m/z 656.5 [(M+H)+; calcd for C38H46N3O7: 656.3].
Reaction SMILES: C(OC([NH:8][C:9]([CH3:30])([CH3:29])[CH2:10][O:11][C:12](=[O:28])[C@H:13]([CH:25]([CH3:27])[CH3:26])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]([CH3:30])([CH3:29])[CH2:10][O:11][C:12](=[O:28])[C@H:13]([CH:25]([CH3:26])[CH3:27])[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(N-(tert-butyloxycarbonyl)-amino)-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propane (10 g, 23 mmole) in dichloromethane (150 ml) was added trifluoroacetic acid (30 ml) and the mixture was stirred for 1 hour at room temperature. The solution was evaporated under reduced pressure and 10% sodium carbonate solution was added. The product was extracted four times with dichloromethane, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with dichloromethane/methanol. Yield: 3.0 g=40% (crude)