Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.O>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: Fc1ncccc1C1CCOCC1
Reactant: O=C(c1ccc(O)cc1)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1ccc(Oc2ncccc2C2CCOCC2)cc1)c1ccccn1
Temperature: 180 °C

Procedure:
A glass microwave reaction vessel was charged with 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (0.4000 g, 2.207 mmol), (4-hydroxyphenyl)(pyridin-2-yl)methanone (0.660 g, 3.31 mmol), and cesium carbonate (2.158 g, 6.62 mmol) in N-Methyl-2-pyrrolidinone (7.36 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 180° C. for 30 min. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was washed with water, sat NaCl, dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography to give the title compound. MS (ESI, pos. ion) m/z: 361.0 (M+1). IC50 (uM) 0.5561.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)cc1
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: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc(F)cc2)cc1
Yield: 69.4 %

Procedure:
A solution of 4-bromobenzaldehyde (1.0 g, 5.4 mmol, 1.0 eq) and 4-fluorophenylboronic acid (0.75 g, 5.4 mmol, 1.0 eq) in toluene was purged with nitrogen for 15 minutes and degassed under vacuum. Dry K2CO3 (1.12 g, 8.12 mmol, 1.5 eq) and tetrakis catalyst (0.3 g, 0.27 mmol, 0.05 eq) were added under nitrogen. The reaction mixture was refluxed under nitrogen for 12 h, quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under vacuum. The residue was purified by silica gel (60-120) column chromatography using 5-10% ethyl acetate/hexane as the eluent to afford the desired compound (0.75 g, 75%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.35 (t, 2H), 7.77-7.83 (t, 2H), 7.86-7.88 (d, 2H), 7.96-7.98 (d, 2H), 10.03 (s, 1H). MS (ESI): 201.2 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH3:30])[CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[CH:19][N:18]=2)=[O:16])=[C:10](Cl)[CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]I>[CH:26]1([CH2:25][O:24][C:20]2[C:21]([F:23])=[CH:22][C:17]([C:15]3[O:16][C:10]4[CH:9]=[C:8]([O:7][CH2:6][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH3:30])[N:13]=[CH:12][C:11]=4[N:14]=3)=[N:18][CH:19]=2)[CH2:28][CH2:27]1
Reactant: CC(=O)N[C@@H](C)COc1cc(Cl)c(NC(=O)c2cc(F)c(OCC3CC3)cn2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCC4CC4)cn3)nc2cn1
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 5.9 %

Procedure:
A suspension of N-(6-(((2S)-2-acetamidopropyl)oxy)-4-chloropyridin-3-yl)-5-(cyclopropylmethoxy)-4-fluoropyridine-2-carboxamide (1.05 g), potassium carbonate (664 mg) and copper(I) iodide (46.0 mg) in DMF (10 mL) was stirred at 160° C. for 1.5 hr. To the reaction mixture was added water, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and subjected to silica gel chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (56.9 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])=[CH:46][CH:45]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc1
Yield: 71.4 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in dimethoxyethane (5.6 mL), and the solution was added with 4-methoxyphenylboronic acid (62 mg, 0.41 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (13.2 mg, 0.0166 mmol), potassium carbonate (93.0 mg, 0.675 mmol) and water (0.049 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=8/1) to obtain 4-(4-methoxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (53.2 mg, yield 71%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:14]3[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]=4[N:17]=[CH:18][C:13]=3[C:12](=[O:30])[NH:11][C:10]2=[O:31])[CH2:5][CH2:4]1.I(C1C=CC=CC=1C(O)=O)(=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CS(C)=O>[O:31]=[C:10]1[N:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH:2]=[O:1])[CH2:4][CH2:5]2)[C:14]2[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:16]=3[N:17]=[CH:18][C:13]=2[C:12](=[O:30])[NH:11]1
Reactant: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)[nH]c(=O)n([C@H]3CC[C@H](CO)CC3)c12
Agent: O=C(O)c1ccccc1I(=O)=O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)[nH]c(=O)n([C@H]3CC[C@H](C=O)CC3)c12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1-[trans-4-(Hydroxymethyl)cyclohexyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-2,4(3H,7H)-dione (107 mg, 0.240 mmol) in a mixture of toluene (1 mL) and dimethyl sulfoxide (0.25 mL) was mixed with 2-iodoxybenzoic acid (80.9 mg, 0.288 mmol) and stirred at 50° C. for 2 hours. After addition of saturated aqueous sodium thiosulfate and saturated aqueous sodium hydrogen carbonate, the reaction mixture was stirred at room temperature for 30 minutes, and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1→7/3 (v/v)) to give the title compound as a colorless solid (70.1 mg, yield 66%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([O:53][C:54]([N:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[C:57]1[C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([NH2:71])[CH:66]=1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C>[C:49]([O:53][C:54]([N:56]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[C:57]1[C:65]1[CH:70]=[CH:69][CH:68]=[C:67]([NH:71][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:66]=1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: CC(C)(C)OC(=O)n1c(-c2cccc(N)c2)cc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1c(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc2ccccc21
Temperature: 25 °C
Yield: 62 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2-(3-Amino-phenyl)-indole-1-carboxylic acid tert-butyl ester (0.02 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.02 g of product in 64% yield: LCMS (ESI) m/z 497 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=2[CH:10]=[C:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.Cl.[C:27]([NH2:30])(=[NH:29])[CH3:28].C(N(CC)CC)C.C(OCC)(=O)C>C(O)CCC>[ClH:1].[CH3:28][C:27]1[NH:30][CH:10]([C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[O:7][CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([CH3:19])[N:29]=1
Reactant: CCOC(=O)C(=Cc1ccccc1OCc1ccc(Cl)cc1)C(C)=O
Reactant: CC(=N)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)N=C(C)NC1c1ccccc1OCc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 40.4 %

Procedure:
A mixture of ethyl 2-[2-(4-chlorobenzyloxy)-benzylidene]acetoacetate (10 g), acetamidine hydrochloride (3.16 g), and triethylamine (4.23 g) in n-butanol (100 ml) was refluxed for 3.5 hours. The reaction mixture, added ethyl acetate (100 ml), was washed with water (100 ml) and 5% hydrochloric acid (100 ml) successively. The solvent was evaporated and the residual crystalline was stirred with ethyl acetate (50 ml) for 1 hour. The crystals were collected by filtration dried in vacuo to afford ethyl 2,4-dimethyl-6-[2-(4-chlorobenzyloxy)phenyl]-1,6-dihydro-5-pyrimidinecarboxylate hydrochloride (2.45 g).
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7])[CH3:3].[Na+].[I-:11]>CC#N>[I:11][CH:2]([O:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7])[CH3:3]
Reactant: [I-]
Reactant: CC(Cl)OC(=O)C(C)C
Agent: [Na+]
Solvent: CC#N
Product: CC(I)OC(=O)C(C)C
Temperature: 25 °C
Yield: 45.9 %

Procedure:
To a solution of the chloro compound from Step 1 (2.6 g, 17.3 mmol) in CH3CN (20 mL) at r.t. was added NaI (2.85 g, 19 mmol). The flask was covered with Al foil and the reaction was stirred ON at r.t. The orange suspension was filtered and the filtrate was evaporated to dryness. The crude product was dissolved in Et2O/H2O and the organic phase was washed with aqueous sodium metabisulfite and brine. After drying (MgSO4), filtering, and removal of solvent, a pale brown oil (1.92 g) was obtained.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH2:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]([O:26]C)=[O:25])[C:16]=2[O:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.O>CO>[O:1]([CH2:8][C:9]([NH:11][CH2:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=2[O:15][CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1cccc2c(CNC(=O)COc3ccccc3)coc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COc1cccc2c(CNC(=O)COc3ccccc3)coc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Methyl (3-((phenoxyacetylamino)methyl)benzofuran-7-yloxy)acetate (126 mg) was dissolved in methanol (5 ml) and 1N aqueous sodium hydroxide solution (0.5 ml) was added to the obtained solution, followed by stirring the resulting solution at room temperature for 1 hour. To the reaction solution, 1N hydrochloric acid (1 ml) was added and the solution was poured into water layer (30 ml), followed by extracting the resultant twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was recrystallized from cyclohexane/ethyl acetate to obtain the desired compound (108 mg, yield: 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[C:4](C(Cl)(Cl)Cl)[CH:3]=1.ClC1C=CC=CC=1C(C1C=CC=CC=1Cl)(O)[C:29](Cl)([Cl:31])[Cl:30]>>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][CH:15]=2)[CH:29]([Cl:31])[Cl:30])=[CH:12][CH:11]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1C(Cl)(Cl)Cl
Reactant: OC(c1ccccc1Cl)(c1ccccc1Cl)C(Cl)(Cl)Cl
Product: Clc1ccc(C(c2ccc(Cl)cc2)C(Cl)Cl)cc1

Procedure:
4,4'-dichloro-2-(trichloromethyl) benzhydrol or 1,1-bis(chlorophenyl)2,2,2-trichloroethanol;
Reaction SMILES: C(O[C@H:5]([CH2:8][CH2:9][C@@H:10]([OH:23])[CH2:11][O:12]S(C1C=CC(C)=CC=1)(=O)=O)[C:6]#[CH:7])(=O)C.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CO>[C:6]([C@@H:5]1[O:23][C@@H:10]([CH2:11][OH:12])[CH2:9][CH2:8]1)#[CH:7]
Reactant: C#C[C@@H](CC[C@@H](O)COS(=O)(=O)c1ccc(C)cc1)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C#C[C@H]1CC[C@H](CO)O1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a solution of (3R,6R)-3-acetoxy-6-hydroxy-7-p-toluene sulfonyloxy-hept-1-yne 31 (0.6 g, 1.76 mmol) in MeOH (10 mL) at room temperature, K2CO3 (0.536 g, 3.88 mmol) was added and the mixture was stirred for 2 h. It was treated with NH4Cl solution, evaporated MeOH and the residue extracted with EtOAc (3×20 mL). Organic layer was washed with water (10 mL), brine (10 mL), dried (Na2SO4) evaporated. The residue obtained was purified by column chromatography (Si-gel, 20% EtOAc-hexane) to furnish (2R,5R)-5-ethynyl-2-(hydroxymethyl)-tetrahydrofuran 32 (0.22 g) in 99% yield as a colorless liquid. [α]D+20.0 (c 1.0, CHCl3); 1HNMR (CDCl3, 200 MHz): δ 1.89-2.38 (m, 4H, H-3,4), 2.4 (br.s, 1H, OH), 2.46 (d, 1H, J 2.2 Hz, H-7), 3.55 (dd, 1H, J 4.5, 11.25 Hz, H-1), 3.72 (dd, 1H, J 4.0, 11.25 Hz, H-1a), 4.0-4.15 (m, 1H, H-2), 4.52-4.66 (m,1H, H-5); 13CNMR (CDCl3, 50 MHz): δ 26.6, 29.6, 33.6, 64.6, 68.3, 73.0, 80.7; EIMS m/z (relative intensity): 125 (M+−1, 8), 95 (74.6), 67 (100), 53 (40), 41 (80); HRMS: Calculated for C7H9O2 (M−1): 125.060255; Observed: 125.060322.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:30])=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]=[C:11]([CH3:17])[N:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](=[O:28])(=[O:27])[NH:25][CH3:26])[C:9]2=[O:29])=[O:5])[CH3:2].C(O[C:34](=O)[C:35]1C(C)=CC(NC(=O)C)=C(C(O)=O)[C:36]=1C)C.NC1C=CC=CC=1S(NC)(=O)=O.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH:2]1([CH2:1][O:3][C:4]([C:6]2[C:7]([CH3:30])=[C:8]3[C:13](=[CH:14][C:15]=2[CH3:16])[N:12]=[C:11]([CH3:17])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24](=[O:28])(=[O:27])[NH:25][CH3:26])[C:9]3=[O:29])=[O:5])[CH2:36][CH2:35][CH2:34]1
Reactant: CCOC(=O)c1c(C)cc(NC(C)=O)c(C(=O)O)c1C
Reactant: CCOC(=O)c1c(C)cc2nc(C)n(-c3ccccc3S(=O)(=O)NC)c(=O)c2c1C
Agent: CNS(=O)(=O)c1ccccc1N
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: CNS(=O)(=O)c1ccccc1-n1c(C)nc2cc(C)c(C(=O)OCC3CCC3)c(C)c2c1=O
Temperature: 140 °C

Procedure:
Preparation of 2,5,7-Trimethyl-3-(2-methylsulfamoyl-phenyl)-4-oxo-3,4-dihydro-quinazoline-6-carboxylic acid ethyl ester: A heterogeneous mixture of 4-Acetylamino-2,6-dimethyl-isophthalic acid 1-ethyl ester (5.39 g, 1.95 mmol), 2-amino-N-methyl-benzenesulfonamide (3.63 g, 1.95 mmol), and phosphorus trichloride (8.5 mL, 9.7 mmol) in toluene (220 mL) was heated at 140° C. (oil bath temperature) for 3.5 h. The reaction mixture was allowed to cool to room temperature and then evaporated in vacuo. Sufficient ethyl acetate was added to dissolve the residue and the solution was washed with saturated aqueous sodium hydrogen carbonate then brine, dried (Na2SO4) and evaporated in vacuo. Trituration of the residue with dichloromethane gave a white solid, which was removed by filtration. Evaporation of the filtrate solution followed by trituration with ethyl acetate provided a second crop of white solid. The evaporation-trituration procedure was repeated to give two further crops of white solid. The combined white solids were washed with ether and dried in vacuo to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCN(Cc2cn(C)c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN5CCC(C(=O)O)CC5)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of ethyl 1-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-4-piperidinecarboxylate (D79) (308 mg) in tetrahydrofuran (5 mL) and ethanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (60 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated and then H2SO4 (0.1 M) solution was added dropwise until no further white precipitate was formed. The solid was filtered and recrystallized from EtOAc to afford 1-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-4-piperidinecarboxylic acid (E57) (140 mg). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 1.49-2.21 (7H, m), 2.84-2.87 (2H, m), 3.65 (5H, s), 4.86-4.93 (1H, m), 7.18 (1H, t), 7.31 (1H, s), 7.44 (1H, dd), 7.46 (1H, d), 7.91 (1H, dd), 8.14 (1H, dd), 8.21 (1H, d), 12.06 (1H, br s). MS (ES): C27H29ClN4O4 requires 508; found 380.1 (M—NC5H9COOH+).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[F:6][C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10]>C(Cl)Cl>[Cl:4][CH:11]([C:9](=[O:10])[C:8]1[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=1[F:6])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)c1ccccc1F
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
Sulfuryl chloride (4.25 g, 32 mmol) was added dropwise to a solution ethyl 2-(2-flurobenzoyl)acetate (6.30 g, 30 mmol) in CH2Cl2 (75 mL) at room temperature. No exotherm was observed after 30 minutes, only slight bubbling. After stirring overnight TLC analysis indicated that all of the starting material had been consumed. The reaction mixture was treated with H2O (100 mL). The resultant mixture was stirred for 20 minutes and the phases were separated. The organic phase was washed with H2O (2×100 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 6.85 g (93% yield) of the desired product as an orange oil: 1H NMR (CDCl3) δ8.0-7.9 (m, 1H), 7.6-7.5 (m, 1H), 7.3-7.1 (m, 2H), 5.6 (s, 1H), 4.25 (q, 2H), 1.25 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:19][C:20]1([CH3:45])[CH:29]=[C:28]([CH3:30])[C:27]2[N:26]=[CH:25][N:24]=[C:23]([N:31]3[CH2:37][C:36]4[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:35]=4[O:34][CH2:33][CH2:32]3)[C:22]=2[CH2:21]1>>[NH2:1][C:2]1[C:7]([S:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][C:5]([C:39]2[CH:40]=[CH:41][C:35]3[O:34][CH2:33][CH2:32][N:31]([C:23]4[C:22]5[CH2:21][C:20]([CH3:19])([CH3:45])[CH:29]=[C:28]([CH3:30])[C:27]=5[N:26]=[CH:25][N:24]=4)[CH2:37][C:36]=3[CH:38]=2)=[CH:4][N:3]=1
Reactant: CN1CC[C@H](NS(=O)(=O)c2cc(Br)cnc2N)C1
Reactant: CC1=CC(C)(C)Cc2c1ncnc2N1CCOc2ccc(B(O)O)cc2C1
Product: CC1=CC(C)(C)Cc2c1ncnc2N1CCOc2ccc(-c3cnc(N)c(S(=O)(=O)N[C@@H]4CCN(C)C4)c3)cc2C1

Procedure:
Synthesized according to the method of example 5 using (S)-2-amino-5-bromo-N-(1-methylpyrrolidin-3-yl)pyridine-3-sulfonamide (reagent preparation 25) and [4-(6,6,8-trimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.52 (d, 1H), 8.37 (s, 1H), 8.12 (s, H), 8.06 (d, 1H), 7.56 (d, 1H), 7.45 (dd, 1H), 7.02 (d, 1H), 6.69 (br s, 2H), 6.12 (s, 1H), 4.62 (s, 2H), 4.32 (br t, 2H), 3.84 (br m, 2H), 3.63 (br s, 1H), 2.68 (s, 2H), 2.44 (m, 2H), 2.26-2.16 (m, 2H), 2.14 (s, 3H), 1.88 (s, 3H), 1.86 (s, 2H), 1.48-1.42 (m, 1H), 0.91 (s, 6H); MS (EI) for C30H37N7O3S: 576 (MH+).
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].ClC1C=C(Cl)C(Cl)=CC=1[O:17][C:18](=O)[C@@H:19]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1>CN(C)C=O>[CH2:1]([NH:7][C:18](=[O:17])[C@@H:19]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1CC[C@@H](C(=O)Oc2cc(Cl)c(Cl)cc2Cl)N1
Reactant: CCCCCCN
Solvent: CN(C)C=O
Product: CCCCCCNC(=O)[C@@H]1CCC(=O)N1
Reaction time: 20 h

Procedure:
4 ml of n-hexyl amine were added at 0° C. to a solution of 3.1 g of L-pyroglutamic acid 2,4,5-trichlorophenyl ester in 10 ml of dimethyl formamide and the solution was left at room temperature for 20 hours. The solvent was removed by distillation in vacuo at room temperature. The residue was taken up in 90% aqueous methanol, and the solution was filtered successively through 200 ml each of Levatit S 100(H+ -form)and Serdolit Blau (OH- -form). The ion exchanger columns were washed with 200 ml of 90% methanol and the combined eluate and washing solution were concentrated in vacuo. The L-pyroglutamic acid n-hexyl amide obtained as a colorless solid was recrystallized from ethyl acetate.
Reaction SMILES: C([Mg]Cl)(C)C.[N:6]1([C:12]2[S:13][C:14]3[C:19](=[O:20])[N:18]=[CH:17][NH:16][C:15]=3[N:21]=2)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.BrC[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[C:35]=1[CH3:44].[OH-].[Na+]>O1CCCC1.O.CO>[CH3:44][C:35]1[C:36]([C:40]([F:41])([F:42])[F:43])=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:17][NH:16][C:15]1[N:21]=[C:12]([N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[S:13][C:14]=1[C:19]([NH2:18])=[O:20]
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: O=c1nc[nH]c2nc(N3CCOCC3)sc12
Agent: CC(C)[Mg]Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CNc2nc(N3CCOCC3)sc2C(N)=O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117.4 %

Procedure:
Isopropylmagnesium chloride (1.679 mL, 3.36 mmol) was added to a suspension of 2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (0.8 g, 3.36 mmol) in Tetrahydrofuran (THF) (30 mL) at 0° C. LiHMDS (3.36 mL, 3.36 mmol) was added. The ice bath was removed. The reaction mixture was stirred at RT for 30 min, cooled down to 0° C. 1-(Bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (1 g, 3.95 mmol) was added. The reaction mixture was heated at 60 C overnight. LCMS showed very clean reaction. NaOH (1.12 mL, 6.72 mmol, 6N) was added. The resulting mixture was heated at 60° C. for 1 hr (MeOH may be added to accelerate the reaction). LCMS showed the hydrolysis was almost complete. Water was added, creamy-colored solid was formed, filtered, rinsed with water, and dried under high vacuum at 50° C. to give 1.58 g of product, which may contain inorganic salt.