Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([C:22](=[O:27])NCOC)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH:22]=[O:27])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COCNC(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
[(R)-2-Biphenyl-4-yl-1-(methoxymethylcarbamoyl)ethyl]carbamic acid t-butyl ester (7.5 g, 19.5 mmol, 1.0 eq.) was combined with THF (distilled) (100 mL) under nitrogen. Lithium aluminum hydride (750 mg, 19.8 mmol, 1.0 eq.) was added to the resulting stirred solution in several batches at −5˜0° C. over a period of 30 minutes. The resulting solution was stirred for 30 minutes at −5-0° C. The reaction was then quenched by the addition of a solution of KHSO4 (6.6 g) in water (35 mL). The resulting solution was combined with a 1N HCl (75 mL) solution, and stirred for five minutes. EtOAc (100 mL) was added and the resulting solution was extracted with EtOAc (3×100 mL) and the organic layers were combined to yield the title compound (6.3 g) as a yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH:21]3[CH2:23][CH2:22]3)[N:16]=[CH:17][C:18]=2[CH2:19][OH:20])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C1COCC1.O=[Mn]=O>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]([CH:21]3[CH2:23][CH2:22]3)[N:16]=[CH:17][C:18]=2[CH:19]=[O:20])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(CO)cnn2C2CC2)CC1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2c(C=O)cnn2C2CC2)CC1
Yield: 70.7 %

Procedure:
The above acid (300 mg, 0.894 mmol) was dissolved in 5 mL of THF. To this solution was added 3.58 mL (3.58 mmol) of 1M borane in THF. After stirring for 5 h, the mixture was poured into 15 mL of 5% HCl. The solution was extracted with 200 mL of EtOAc, and the extract was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, concentrated, and chromatographed (10–100 EtOAc in hexanes) to give 120 mg of N-Boc-4-(2-cyclopropyl-4-hydroxymethyl-2H-pyrazol-3-yl)-piperidine. This alcohol (100 mg, 0.31 mmol) was stirred overnight in 10 mL of THF with 270 mg (3.1 mmol) of activated MnO2. The mixture was filtered and concentrated to provide 70 mg of N-Boc-4-(2-cyclopropyl-4-formyl-2H-pyrazol-3-yl)-piperidine.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[C:22]([O:26][C:27](=[O:55])[N:28]([CH2:30][CH2:31][C:32]([NH:34][NH:35][C:36]([C@@H:38]1[CH2:44][CH2:43][C@@H:42]2[CH2:45][N:39]1[C:40](=[O:54])[N:41]2[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=O)=[O:33])[CH3:29])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[CH2:47]([O:46][N:41]1[C:40](=[O:54])[N:39]2[CH2:45][C@H:42]1[CH2:43][CH2:44][C@H:38]2[C:36]1[O:33][C:32]([CH2:31][CH2:30][N:28]([CH3:29])[C:27](=[O:55])[O:26][C:22]([CH3:24])([CH3:25])[CH3:23])=[N:34][N:35]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CN(CCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C(=O)OC(C)(C)C
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(CCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of PPh3 (5.3 g, 20.0 mmol) in CH2Cl2 (250 mL) at rt was added I2(5.2 g, 20.0 mmol). After I2 was dissolved completely, the solution was cooled to 0° C. and TEA (7.0 mL, 50.0 mmol) was added.Tert-butyl3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl) hydrazinyl)-3-oxopropyl(methyl)carbamate (4.8 g, 10.0 mol) was added and the mixture was stirred at rt for 1 hr. The mixture was concentrated, EtOAc (250 mL) was added, and the solution was filtered to remove POPh3. The filtrate was concentrated and the residue was purified by silica gel column chromatography (gradient elution 30 to 50% EtOAc/petroleum ether) to afford tert-butyl 2-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)ethyl(methyl)carbamate (4.1 g, 85%) as a white solid. ESI-MS (EI+, m/z): 458 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:4][C:5]2[O:9][C:8]([C:10]3[O:11][C:12]([CH3:15])=[N:13][N:14]=3)=[C:7]([C:16]([NH:18][CH3:19])=[O:17])[C:6]=2[CH:20]=1.[F:27][C:28]1[C:29]2[CH:30]=[C:31]3[C:40]4[N:41]=[C:42]([Sn](C)(C)C)[CH:43]=[CH:44][C:39]=4[O:38][CH2:37][N:32]3[C:33]=2[CH:34]=[CH:35][CH:36]=1.[Li+].[Cl-]>CC(O)C>[F:27][C:28]1[C:29]2[CH:30]=[C:31]3[C:40]4[N:41]=[C:42]([C:2]5[C:3]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:4][C:5]6[O:9][C:8]([C:10]7[O:11][C:12]([CH3:15])=[N:13][N:14]=7)=[C:7]([C:16]([NH:18][CH3:19])=[O:17])[C:6]=6[CH:20]=5)[CH:43]=[CH:44][C:39]=4[O:38][CH2:37][N:32]3[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: C[Sn](C)(C)c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2
Reactant: CNC(=O)c1c(-c2nnc(C)o2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)O
Product: CNC(=O)c1c(-c2nnc(C)o2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 20.7 %

Procedure:
To a mixture of compound 5-bromo-N-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (70 mg, 0.16 mmol), 11-fluoro-2-(trimethylstannyl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (95 mg, 0.24 mmol) and LiCl (20 mg, 0.47 mmol) in IPA (2 mL), chloro[(tricyclohexylphosphine)-2-(2′-aminobiphenyl)]palladium(II) (50 mg) was added under N2 protection. After stirring at 100° C. overnight, the reaction mixture was concentrated in vacuo. The residue was purified by prep-TLC (DCM:MeOH=100:1) to give the product of 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-N-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (20 mg, yield: 21%). 1H-NMR (CDCl3, 400 MHz) δ 9.81 (br s, 1H), 8.81 (s, 1H), 7.77 (s, 1H), 7.55˜7.46 (m, 2H), 7.25˜7.18 (m, 2H), 7.13 (s, 1H), 6.89˜6.80 (m, 1H), 6.01 (s, 2H), 3.41 (s, 3H), 3.09 (d, J=4.4 Hz, 3H), 2.76 (s, 3H), 2.68 (s, 3H). MS (M+H)+: 603.
Reaction SMILES: [F:1][CH2:2][C:3]([O-])=O.[Na+].C(Cl)(=O)C(Cl)=O.[OH-].[Na+].[Si:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:47]2[CH2:56][CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[C:52]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])[CH:53]=3)[CH2:48]2)=[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[C:33]([F:46])[CH:32]=2)[CH:28]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>ClCCl.CN(C)C=O>[Si:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:47]2[CH2:56][CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[C:52]([O:57][Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:59])[CH3:60])[CH:53]=3)[CH2:48]2)=[C:27]([N:29]([CH2:3][CH2:2][F:1])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[C:33]([F:46])[CH:32]=2)[CH:28]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=C([O-])CF
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1N(CCF)Cc1ccc(OCCN3CCCCC3)c(F)c1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
To a solution of sodium fluoroacetate (420 mg) in dichloromethane (20 ml) were added dropwise N,N-dimethylformamide (1 drop) and oxalyl chloride (0.48 ml) on an ice bath, the solution was stirred for 20 minutes at room temperature, an aqueous solution of 1N sodium hydroxide was added thereto, the solution was stirred for 1 minute at room temperature, then a solution of {5-(tert-butyldimethylsilyloxy)-2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]phenyl}[3-fluoro-4-(2-piperidin-1-yl-ethoxy)benzyl]amine (300 mg) in dichloromethane (5 ml) was added thereto followed by stirring at room temperature for 3 hours. The solution extracted with dichloromethane, then washed with brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. Synthesized from the resulting residue according to an analogous synthetic method to Example 337 described below, the title compound (200 mg) was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([NH:18][C:19]([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[O:20])=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1.ClCCl>[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[S:34]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([NH:18][C:19]([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[O:20])=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1ccc(-c2ccc3c(NC(=O)c4ccsc4)n[nH]c3c2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1n[nH]c2cc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)ccc12)c1ccsc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
A solution of 1.72 g of 6-(4-aminophenyl)-3-[(thiophen-3-yl)carbonylamino]-1H-indazole hydrochloride in 69 mL of pyridine is admixed at 0° C. with a solution of 1.14 g of 2,3-dichlorobenzenesulfonyl chloride in 23 mL of dichloromethane. The reaction mixture is stirred for 3 hours at a temperature in the region of 20° C. and then concentrated under reduced pressure. The dry residue is diluted in ethyl acetate, washed with water and then washed with saturated sodium chloride solution and concentrated under reduced pressure. The foam obtained is purified by flash chromatography, eluting with a dichloromethane/methanol/acetonitrile (96/2/2 by volume) mixture, to give 0.69 g of 3-thiophenecarboxylic acid {6-[4-(2,3-dichlorobenzenesulfonylamino)phenyl]-1H-indazol-3-yl}amide, whose characteristics are as follows:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26]C)=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O.Cl>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([OH:26])=[O:25])=[C:12]2[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Cn1c(C(=O)O)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 96.7 %

Procedure:
To a suspension of methyl 6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (5.00 g, 10.5 mmol) in 1,4-dioxane (50 ml) was added an aqueous solution (20 ml) of lithium hydroxide monohydrate (1.32 g, 31.5 mmol). The obtained mixture was refluxed under heating for 24 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained, crystals were recrystallized from tetrahydrofuran-n-hexane to give 6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (4.69 g, 96.7%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O>Cl.O>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: O
Product: Nc1ccc2c(c1)C(=O)OC2
Yield: 83.8 %

Procedure:
To a solution of 6-nitroisobenzofuran-1(3H)-one (15.0 g, 0.0800 mol) in HCl/H2O (375 mL/125 mL) was added SnCl2-2H2O (75.0 g, 0.330 mol). The reaction mixture was heated at reflux for 4 h, quenched with water, and extracted with ethyl acetate (300 mL×3). The organic layer was dried over Na2SO4 was evaporated in vacuo to give 6-aminoisobenzofuran-1(3H)-one (10.0 g, 78%). 1H NMR (300 MHz, CDCl3) δ 7.23 (d, J=8.1, 1H), 7.13 (d, J=2.1, 1H), 6.98 (dd, J=8.1, 2.1, 1H), 5.21 (s, 2H), 3.99 (br s, 2H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:54](=[O:55])[N:6]2[C:7]([C:41]([O:43]CC3C=CC([N+]([O-])=O)=CC=3)=[O:42])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15]([CH3:17])[C@H:14]([C:18]([N:20]4[CH2:23][CH:22]([N:24](C(OCC5C=CC([N+]([O-])=O)=CC=5)=O)[C:25](=[NH:27])[CH3:26])[CH2:21]4)=[O:19])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[H][H]>O1CCCC1.O.[Pd]>[C:25]([NH:24][CH:22]1[CH2:21][N:20]([C:18]([C@@H:14]2[CH2:13][C@H:12]([S:11][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:54](=[O:55])[N:6]4[C:7]=3[C:41]([OH:43])=[O:42])[CH2:16][N:15]2[CH3:17])=[O:19])[CH2:23]1)(=[NH:27])[CH3:26]
Reactant: CC(=N)N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: CC(=N)NC1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C)C1
Yield: 61.4 %

Procedure:
453 mg of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-methyl-2-[3-[N-(4-nitrobenzyloxycarbonyl)-N-acetimidoylamino]azetidin-1-ylcarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] were dissolved in 21 ml of a 2:1 by volume mixture of tetrahydrofuran and water, and 500 mg of a 10% w/w palladium-on-carbon catalyst were added to the resulting solution. The mixture was then hydrogenated at room temperature for 1.5 hours in an atmosphere of hydrogen. The catalyst was then removed by filtration, and the filtrate was washed with diethyl ether. The aqueous layer was concentrated by evaporation under reduced pressure. The residue was subjected to reverse phase column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 40 ml). Of the fractions obtained by solution with 8% by volume aqueous acetonitrile, the one containing the title compound was concentrated by evaporation under reduced pressure and freeze-dried, to give 166 mg of the title compound as a powder.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@H:17]([CH2:25][OH:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][C@H:17]([CH2:25][OH:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@H](CO)Cc1ccccc1
Yield: 35 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with L-phenylalaninol to provide the title compound in 35% yield as yellow needles (recrystallization from acetone/CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH2:17][O:18][CH3:19])[NH:11][C:10](=[O:20])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:31]1([CH:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:28][CH2:29][NH:30][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:20])[NH:11][C:12]=2[CH2:17][O:18][CH3:19])=[O:16])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: COCC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COCC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
130 mg (0.438 mmol) of 4-(3-chlorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 139 mg (0.657 mmol) of 3,3-diphenylpropylamine were dissolved in 10 ml of DMF. 126 mg (0.657 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1) to obtain the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C@@H:10]([NH:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1)[CH2:11][CH2:12][CH3:13].O>C(Cl)(Cl)Cl>[Br:1][C:20]1[N:21]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:22]2[C:18]([N:19]=1)=[C:17]([NH2:30])[N:16]=[C:15]([NH:14][C@H:10]([CH3:9])[CH2:11][CH2:12][CH3:13])[N:23]=2
Reactant: CCC[C@@H](C)Nc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC[C@@H](C)Nc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Yield: 29.6 %

Procedure:
N-Bromosuccinimide (2.08 g, 11.69 mmol) was added portionwise to a stirred solution of N2-[(1R)-1-methylbutyl]-9-(tetrahydro-2H-pyran-2-yl) -9H-purine-2,6-diamine (2.27 g, 7.46 mmol) in chloroform (30 ml) at 0° C. under at atmosphere of nitrogen. The reaction mixture was allowed to stir for 1.5 hours when chloroform (20 ml) and water (50 ml) were added. After mixing the layers were separated using a hydrophobic frit, the aqueous layer was washed with an additional portion of chloroform and the combined organic extracts were evaporated. The residue was dissolved in dichloromethane and purified on a 110 g aminopropyl (NH2) cartridge using a 0-100% ethyl acetate in cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as an off-white foam (0.846 g).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=1)[C:10]([O:12][CH3:13])=[O:11])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[C:6]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=1)[C:10]([O:12][CH3:13])=[O:11])#[CH:5]
Reactant: COC(=O)c1ccnc(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1cc(C(=O)OC)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-((trimethylsilyl)ethynyl)isonicotinate (1125) (8.00 g, 34.2 mmol) in THF (150 mL) was added TBAF (1.0 M in THF) (51.4 mL, 51.4 mmol) at 0° C. The resulting solution was allowed to warm to room temperature at which stirring was continued for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 10% NaHCO3 (50 mL). The organic layer was dried (MgSO4) and evaporated under reduced pressure to give a dark brown/black residue. The residue was adsorbed onto silica gel and purified by chromatography (SiO2, 0-20% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I126) (4.5 g, 81%) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.73 (dd, J=5.1, 0.9 Hz, 1H), 8.01 (dd, J=1.5, 0.9 Hz, 1H), 7.80 (dd, J=5.1, 1.6 Hz, 1H), 3.95 (s, 3H), 3.22 (s, 1H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][C:9]1[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:14]([C:12]1[S:13][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: OCCNCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)s1)N(CCO)CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a stirred solution of diethanolamine (1.45 g, 13.8 mmol) in THF (20 mL) was added at 0° C. (ice water bath) commercially available 5-chloro-thiophene-2-sulfonyl chloride (1.0 g, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (1.15 g, 88%) as a white solid. MS (ISN) 284.3 [(M−H)−], mp 69° C.
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[CH:25]4)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13].Br[CH2:30][C:31]([O:33]CC)=[O:32]>C(OCC)C.C1(C)C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:30][C:31]([OH:33])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:13])[CH3:14]
Reactant: CCOC(=O)CBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4cc[nH]c34)no2)cc1Cl
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To methylmagnesium bromide solution (3 mol/L in diethyl ether, 0.4 mL) stirred under nitrogen at 0° C. was added a solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D51) (354 mg) in diethyl ether (5 mL) dropwise. The reaction mixture was stirred at 0° C. for 30 mins. Ethyl bromoacetate (0.13 mL) in toluene (15 mL) was added dropwise. The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with saturated ammonium chloride solution; the organic layer was separated and the solvent was evaporated off. The residue was dissolved in tetrahydrofuran (5 mL) and sodium hydroxide (40 mg) in water (5 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. Evaporated off the organic solvent, extracted with ether (100 mL), the water layer was separated and acidified with HCl (1 M) to pH around 1. The solid was filtered and purified by Mass Directed Auto Prep to afford [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]acetic acid (E31) (86 mg) as a yellow solid. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 3.74 (2H, s), 4.87-4.93 (1H, m), 7.22 (1H, t), 7.40 (1H, d), 7.45 (1H, d), 7.78 (1H, d), 7.95 (1H, d), 8.21 (1H, dd), 8.37 (1H, d), 10.91 (1H, s), 12.19 (1H, br s). MS (ES): C21H18ClN3O4 requires 411; found 412.1 (M+H+).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([NH:7][CH2:8][CH3:9])[CH3:6].[C:10]1([C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][O:12]1)=[O:11].O>ClC(Cl)C>[CH2:5]([N:7]([CH2:8][CH3:9])[C:10](=[O:11])[C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:13][OH:12])[CH3:6]
Reactant: O=C1OCc2ccccc21
Reactant: CCNCC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: CCN(CC)C(=O)c1ccccc1CO
Reaction time: 0.42 h

Procedure:
To a suspension of aluminium trichloride (12.67 g, 94.98 mmol) in dichloroethane (40 mL) is added diethylamine (13.5 g, 182.7 mmol) in dichloroethane (20 mL) while the temperature is maintained below 25° C. with an ice-bath. After another 25 min at r.t., phthalide (10.00 g, 74.5 mmol) is added in three portions and formation of a precipitate is observed. After 45 min, water and ice are added and the mixture is stirred for 30 min and filtered through celite. The aqueous phase is extracted with dichloromethane. After drying the combined organic phase over MgSO4 and filtering through a cotton plug, the volatiles are removed in vacuo to give an orange residue, which is purified by silica gel flash chromatography (dichloromethane-methanol, 49:1 to 97:3 to 19:1) to give N,N-diethyl-2-hydroxymethyl-benzamide as an orange oil; 1H NMR (400 MHz) δ 1.09 (3 H, t, J=7.0 Hz), 1.28 (3 H, t, J=7.0 Hz), 3.24 (2 H, q, J=7.0 Hz), 3.55 (1 H, t, J=6.8 Hz), 3.58 (2 H, q, J=7.0 Hz), 4.52 (2 H, d, J=6.8 Hz), 7.24 (1 H, dd, J=7.4, 1.5 Hz), 7.32 (1 H, td, J=7.4, 1.5 Hz), 7.39 (1 H, td, J=7.4, 1.5 Hz), 7.44 (1 H, td, J=7.4, 1.5 Hz).