Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]3=[O:20])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:21](O)(=O)[CH3:22].C(OC(=O)C)(=O)C.[Cl:32]([OH:36])(=[O:35])(=[O:34])=[O:33]>C(OCC)C>[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]4[C:12](=[O:20])[CH2:13][C:14]([CH3:18])([CH3:19])[CH2:15][C:16]=4[O+:17]=[C:21]([CH3:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CC(=O)O
Reactant: CC1(C)CC(=O)C(c2c[nH]c3cc(F)ccc23)C(=O)C1
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: Cc1[o+]c2c(c3c1[nH]c1cc(F)ccc13)C(=O)CC(C)(C)C2
Product: [O-][Cl+3]([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
2-(6-Fluoro-1H-indol-3-yl)-5,5-dimethylcyclohexane-1,3-dione of Example 3a (0.575 g, 2.1 mmol) was slowly added at room temperature under stirring to a freshly prepared mixture of acetic acid (2 mL), acetic anhydride (2.1 mL) and 70% aqueous perchloric acid (0.17 mL). The reaction mixture was stirred at room temperature for 4 h, diethyl ether (5 mL) was added, and the product was filtered off, washed with diethyl ether and dried at room temperature to give 0.72 g (89%) of the bright yellow crystals. The product was used in the next step without purification.
Reaction SMILES: C([O:3][P:4]([CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])=[O:12])([O:6]CC)=[O:5])C.Br[Si](C)(C)C>C(#N)C>[P:4]([CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])=[O:12])([OH:5])([OH:6])=[O:3]
Reactant: CCOP(=O)(CNC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: O=C(NCP(=O)(O)O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a solution of 0.53 g (1.49 mmol) 2-(diethylphosphonomethylaminocarbonyl)-7-nitroindole in 7 mL acetonitrile was added 2 mL of bromotrimethylsilane at 0° C. The reaction mixture was allowed to stir at room temperature overnight. The solvent and excess bromotrimethylsilane were removed under reduced pressure and 10 mL of a 1/1 mixture of acetone/water was added and stirred for 24 hours at room temperature. A precipitate formed and the solid was filtered and dried to give 0.45 g (1.47 mmol, 99%) of 2-(phosphonomethylaminocarbonyl)-7-nitroindole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]=[O:17]>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH2:16][OH:17])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1ccc(-n2ccnc2)cc1[N+](=O)[O-]
Reactant: C=O
Solvent: O
Product: Cc1ccc(-n2ccnc2CO)cc1[N+](=O)[O-]
Reaction time: 9 h

Procedure:
In a sealed tube, 12 g of 1-(4-methyl-3-nitrophenyl)-imidazole was reacted with 12 ml of 37% formalin at 140° C. for 12 hours, and 6 ml of 37% formalin was further added and reaction was conducted for 9 hours under the same conditions as described above. The reaction mixture was cooled and water was added thereto. The precipitated crystal was recovered by filtration, dried and recrystallized from dimethyl formamide to obtain 10.2 g of the intended compound having a melting point of 185° C. Elementary analysis values as C11H11N3O4 were as follows.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClC1C=CC=CC=1Cl>[Cl:3][C:2]1[N:4]=[C:5]([C:18]2[CH:19]=[CH:20][C:15]([CH3:21])=[CH:16][CH:17]=2)[N:7]=[C:8]([C:18]2[CH:19]=[CH:20][C:15]([CH3:21])=[CH:16][CH:17]=2)[N:1]=1
Reactant: Cc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(-c2nc(Cl)nc(-c3ccc(C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring mixture of 1 eq of cyanuric chloride and 3 eq of aluminum chloride in o-dichlorobenzene at ice bath temperature was added concentrated HCl (13 wt % based on cyanuric chloride). After 10 minutes, 1.9 eq of toluene was added and the reaction mixture was stirred at ice bath temperature for 30 minutes. The cooling bath was removed, the reaction mixture was allowed to warm to room temperature, and stirred for 21 h. HPLC analysis indicated about 95% cyanuric chloride conversion to 2-chloro-4,6-bis(4-methylphenyl)-1,3,5-triazine and the isomer 2-chloro-4-(4-methylphenyl)-6-(2-methylphenyl)-1,3,5-triazine.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:20])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C@@H:3]([OH:20])[CH2:2][NH:1][CH:44]2[CH2:43][CH2:42][N:41]([C:38]3[CH:37]=[CH:36][C:35]([S:32]([NH:31][C:25]4[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=4)(=[O:33])=[O:34])=[CH:40][CH:39]=3)[CH2:46][CH2:45]2)=[CH:7][CH:8]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Reactant: NCC(O)COc1ccc(OCc2ccccc2)cc1
Product: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4ccc(OCc5ccccc5)cc4)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 1-Amino-3-(4-benzyloxy-phenoxy)-propan-2-ol and Reference Example 73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 113-121° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.15-1.35 (m, 2H), 1.75-1.90 (m, 2H), 2.50-2.90 (m, 5H), 2.89 (s, 3H), 3.61 (s, 3H), 3.64 (s, 3H), 3.64-3.80 (m, 5H), 5.02 (s, 2H), 6.70-7.00 (m, 9H), 7.30-7.70 (m, 7H); MS (ES) m/z: 648.1 (MH+); HRMS Calcd. for C35H42N3O7S (MH+): 648.2743. Found: 648.2710.
Reaction SMILES: C1(C(N2C3C(=CC(S(N)(=O)=O)=CC=3)CC2)=O)CCCCC1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[Cl:45])[C:39](Cl)=[O:40]>>[Cl:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[Cl:45])[C:39]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([NH2:34])(=[O:32])=[O:33])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)=[O:40]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2
Agent: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C1CCCCC1
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)c1ccc(Cl)c(Cl)c1
Yield: 36.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 55, indoline-5-sulfonamide (Intermediate 54A, 195 mg, 0.98 mmol) and 3,4-dichlorobenzoyl chloride (412 mg, 1.97 mmol) were converted to the title compound (132 mg, 36%) after purification using preparative HPLC. 1H NMR (DMSO-d6) δ 7.92 (d, J=1.1 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.71-7.61 (m, 3H), 7.26 (s, 2H), 4.07 (t, J=8.3 Hz, 2H), 3.16 (t, J=8.2 Hz, 2H); MS(ESI+) m/z 370.8 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>COCCOC>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:25][CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH3:10]
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Reactant: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(CC=Cc1ccccc1)(Cc1cccc2ccccc12)C(=O)OCC
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a solution of 1.50 g of 2-(1-naphthylmethyl)malonic acid diethyl ester in 20 ml of 1,2-dimethoxyethane was added 0.3 g of a 50% sodium hydride (suspension in oil) under cooling, and then the mixture was stirred for 1 hour. To the mixture was added 1.18 g of cinnamyl bromide, and the mixture was heated under reflux for 5 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The ethereal layer was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 1.6 g of 2-cinnamyl-2-(1-naphthylmethyl)malonic acid diethyl ester as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:10]=[CH:9][N:8]=1)=[O:5].[H][H]>CO.C(Cl)Cl.CC(O)=O.[Pt]>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:19][CH:18]=1
Reactant: [H][H]
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COCC(=O)Nc1cc(Oc2ccc(N)cc2)ccn1

Procedure:
A solution of 2-methoxy-N-(4-(4-nitrophenoxy)pyridin-2-yl)acetamide (730 mg, 2.41 mmol) in MeOH/DCM (1:1 v/v, 80 mL) containing AcOH (5 drops) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, RT, 70 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo. The residue was partitioned between DCM (20 mL) and saturated aqueous NaHCO3 solution (10 mL). The organic layer was washed with brine (20 mL) and was dried (MgSO4) and evaporated in vacuo to afford the title compound, Intermediate H1, as a white solid (0.63 g, 91%); Rt 0.88 min (Method 2); m/z 274 (M+H)+ (ES+).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([I:9])=[CH:7][N:6]=[C:5]([Cl:10])[CH:4]=1.C([O-])([O-])=[O:12].[Ca+2]>O1CCOCC1.O>[Cl:10][C:5]1[CH:4]=[C:3]([CH2:2][OH:12])[C:8]([I:9])=[CH:7][N:6]=1.[Cl:10][C:5]1[CH:4]=[C:3]([CH3:2])[C:8]([I:9])=[CH:7][N:6]=1
Reactant: Clc1cc(CBr)c(I)cn1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Cl)ncc1I
Product: OCc1cc(Cl)ncc1I
Temperature: 25 °C

Procedure:
To a stirred solution of crude 4-bromomethyl-2-chloro-5-iodo-pyridine (23 g, 69.3 mmol, 1 eq) in 1,4-dioxane (230 mL) was added suspension of CaCO3 (36.05 g, 360 mmol, 5.2 eq) in water (230 mL) at room temperature. Resulting reaction mixture was refluxed for 10 hours. After complete consumption of starting material, reaction mixture was cooled to room temperature and filtered through celite bed over Buchner funnel. Celite bed was washed with EtOAc (2×100 mL). Combined filtrate was washed with water (100 mL) and aqueous sodium bicarbonate (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford brown solid (22 g, crude). Crude was purified by column chromatography using silica gel (100-200 mesh). Desired compound was eluted at 30% EtOAc in hexane to get title compound as faint yellow solid (1.4 g, impure) and also 11.5 g of 2-chloro-5-iodo-4-methyl-pyridine was recovered. Impure was used as such for next reaction. 1H NMR (400 MHz, CDCl3) δ: 2.1 (t, J=5.64 Hz, 1H), 4.62 (d, J=6.24 Hz, 2H), 7.54 (s, 1H), 8.58 (s, 1H). LC-MS (m/z): 267.7 (M−H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:24]5[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=5[C:31]([NH:34]C=O)([CH3:33])[CH3:32])=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:37])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[OH-].[Na+]>C(O)C>[N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:24]5[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=5[C:31]([NH2:34])([CH3:33])[CH3:32])=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[C:12]([F:37])=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CC(C)(NC=O)c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(N)c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 0 °C
Yield: 72.2 %

Procedure:
Heat a mixture of N-(2-(2-(2-(2-(2-(1H-1,2,3-triazol-1-yl)ethylamino)-5-fluoropyrimidin-4-yl)benzo[b]thiophen-7-yl)-4-fluorophenyl)propan-2-yl)formamide (120 mg, 231 μmol) and sodium hydroxide (5 N, 10 mL, 50 mmol) in ethanol (10 mL) at 80° C. for 3 h. Dilute the mixture with ice water and extract with chloroform/IPA (3/1, 100 mL). Wash the organic phase with water/aqueous saturated sodium chloride, dry over sodium sulfate, and concentrate in vacuo. Purify the crude product by FCC (DCM to chloroform/methanol/ammonium hydroxide 7/3/0.05 as gradient) to give the title compound as a grey solid (82 mg, 75%). MS (ES) m/z 492 [M+1]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[C:3]1[C:16]2[S:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[Si:18]([CH3:21])([CH3:20])[CH3:19])[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C>CC(C)=O>[CH3:1][Si:2]([CH3:23])([CH3:22])[C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[Si:18]([CH3:21])([CH3:20])[CH3:19])[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)c1cccc2c1S(=O)c1c(cccc1[Si](C)(C)C)S2
Solvent: CC(C)=O
Solvent: CC(=O)Cl
Product: C[Si](C)(C)c1cccc2c1Sc1c(cccc1[Si](C)(C)C)S2
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a stirred solution of 4,6-bis(trimethylsilyl)thianthrene-5-oxide (1.67 g, 4.44 mmole) and acetyl chloride (3.80 mL, 53.2 mmole) in acetone (75 mL), KI (17.00 g, 102.0 mmole) was added. After stirring at room temperature for 2 hrs, solvent was removed in vacuo and the residue was extracted with ether. The extract was washed with water and 1 M Na2S2O3 solution, dried with MgSO4, and the solvent was removed in vacuo to afford yellow oil (1.50 g, 86%). The product was eventually crystallized and used without further purification. mp 90˜91° C. (lit. 95˜96° C.). 1H NMR (300 MHz, CDCl3) δ: 7.47 (dd, 2H, J=7.5, 1.5 Hz), 7.42 (dd, 2H, J=7.5, 1.2 Hz), 7.20 (dd, 2H, J=7.5, 7.5 Hz), 0.46 (s, 18H). 13C NMR (125 MHz, CDCl3) δ: 142.4, 139.8, 134.3, 134.0, 129.6, 126.8, 0.52. HR-MS (ESI): calcd. for C18H24S2Si2+Na 383.0750 [(M+Na)+]. found 383.0747.
Reaction SMILES: [C:1]([C:5]1([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:23]3[CH:24]=[C:25]([CH3:35])[C:26]4[O:30][C:29]([C:31](O)=[O:32])=[CH:28][C:27]=4[CH:34]=3)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=2[CH3:36])[O:9][CH2:8][CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.Cl.C[O:43][C:44](=[O:47])[CH2:45][NH2:46]>CN(C1C=CN=CC=1)C>[C:1]([C:5]1([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([C:23]3[CH:24]=[C:25]([CH3:35])[C:26]4[O:30][C:29]([C:31]([NH:46][CH2:45][C:44]([OH:47])=[O:43])=[O:32])=[CH:28][C:27]=4[CH:34]=3)([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:14][C:13]=2[CH3:36])[O:6][CH2:7][CH2:8][O:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc(C)c2oc(C(=O)O)cc2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC2(C(C)(C)C)OCCO2)c(C)c1)c1cc(C)c2oc(C(=O)NCC(=O)O)cc2c1
Yield: 97.1 %

Procedure:
5-{1-[4-(2-tert-Butyl-[1,3]dioxolan-2-ylmethoxy)-3-methyl-phenyl]-1-ethylpropyl}-7-methyl-benzofuran-2-carboxylic acid (180 mg, 0.364 mmol), EDC (105 mg, 0.546 mmol), DMAP (133 mg, 1.09 mmol, and glycine methyl ester hydrochloride (68 mg, 0.55 mmol) are reacted to produce the intermediate followed by hydrolysis analogous to Example 7 to give title compound (195 mg, 97%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[CH:4][C:3]=1[C:10]1[N:14]2[CH:15]=[C:16]([C:19]3[N:26]4[C:22]([O:23][CH:24]=[CH:25]4)=[N:21][C:20]=3[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1.[NH4+].[OH-:35].[OH-:36].[Na+].N>O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:36])=[O:35])=[CH:4][C:3]=1[C:10]1[N:14]2[CH:15]=[C:16]([C:19]3[N:26]4[C:22]([O:23][CH:24]=[CH:25]4)=[N:21][C:20]=3[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(F)c(-c2nnc3ccc(-c4c(-c5ccc(F)cc5)nc5occn45)cn23)c1
Agent: N
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(F)c(-c2nnc3ccc(-c4c(-c5ccc(F)cc5)nc5occn45)cn23)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
To a suspension of 4-fluoro-3-{6-[6-(4-fluorophenyl)-imidazo[2,1-b]oxazol-5-yl]-[1,2,4]triazolo[4,3-a]pyridin-3-yl}-benzonitrile (0.15 g, 0.34 mmol; Example #K.1.19) in water (1 mL) and then was added NH4OH (28-30% in water, 2.0 mL, 51 mmol) and 1M NaOH (1 mL, 1.0 mmol). The reaction mixture was stirred at about 65° C. for about 8 h. Ammonia (0.5 M in 1,4-dioxane, 10 mL) was added and the reaction mixture was stirred about 72 h at about 65° C. The organic solvent was removed under reduced pressure and aqueous layer was buffered with ammonium acetate aqueous solution. The crude material was purified by reverse phase preparative chromatography (Table 1, Method e). The resulting material was purified by trituration with hot MeOH to afford the title compound (0.038 g, 23%) LC/MS (Table 1, Method a) Rt, =1.84 min; MS m/z: 458.1 (M+H)+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29]([OH:31])=O.Cl.[CH3:33][NH:34][OH:35].O>C(Cl)Cl>[OH:35][N:34]([CH3:33])[C:29](=[O:31])[CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[NH:21][C:15]1[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20]
Reactant: CNO
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CN(O)C(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1'-Carbonyl-diimidazole (5.5 g; 34 mmol) is slowly added to a warm solution of 2-[(2,6-dichlorophenyl)-amino]-benzeneacetic acid (6.5 g; 22 mmol) in CH2Cl2 (600 mL) and stirred at room temperature for 2.0 hours when a clear solution is formed. N-Methylhydroxylamine hydrochloride (5.5 g; 66 mmol) is slowly added to the solution and the mixture stirred at room temperature for 48 hours. It is decomposed with water, extracted with CH2Cl2 and dried over Na2SO4. The solvent is evaporated off and the residue flash chromatographed over silica gel (250 g) using 10% EtOH-CH2Cl2 as eluant to give the pure product as white solid which is recrystallized from toluene-CH2Cl2. Yield 2.95 g (41.2%); mp 135°-138° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([SH:9])[CH3:8].Cl[C:11]1[C:20]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[C:19]([CH3:32])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1>CN(C=O)C.O>[CH2:7]([S:9][C:11]1[C:20]([N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[C:19]([CH3:32])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:8]
Reactant: Cc1c(N2C(=O)c3ccccc3C2=O)c(Cl)nc2ccccc12
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc2ccccc2c(C)c1N1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Yield: 78.4 %

Procedure:
2.1 g (15.4 mmol) of K2CO3 and 760 μl (10.3 mmol) of ethanethiol were added in succession to a solution of 2.1 g (5.1 mmol) of 2-(2-chloro-4-methylquinolin-3-yl)isoindoline-1,3-dione in DMF (36 ml). The mixture was then heated for 16 h at 60° C. A further 2.1 g (15.4 mmol) of K2CO3 and 760 μl (10.3 mmol) of ethanethiol were then added, and the mixture was again heated for 16 h at 50° C. After cooling to RT, the mixture was diluted with water and extracted twice with EA. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. There were obtained as residue 1.7 g (4.0 mmol, 78%) of 2-(2-(ethylthio)-4-methylquinolin-3-yl)isoindoline-1,3-dione, which was reacted further without additional purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1([CH3:14])[CH2:13][O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)C>O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:14][C:11]([OH:12])([CH3:13])[CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: CC1(CCOCc2ccccc2)CO1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(O)(CCOCc1ccccc1)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
2-[2-(Benzyloxy)ethyl]-2-methyloxirane (2.60 g, 13.5 mmol), 4-(4-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (4.14 g, 14.9 mmol), tripotassium phosphate (1.15 g, 5.4 mmol) and ethanol (26 ml) were mixed and stirred at 80 to 90° C. overnight. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→30:70) to afford the title compound as a pale yellow oil (6.16 g).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:7][CH:8]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:28])C=1>ClCCl>[C:1]([C:3]1[C:4](=[O:19])[NH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:16])=[O:28])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(SC)ccc1-c1ccc(C#N)c(=O)[nH]1
Solvent: ClCCl
Product: COc1cc(S(C)=O)ccc1-c1ccc(C#N)c(=O)[nH]1

Procedure:
A solution of 3-cyano-6-(2-methoxy-4-methylthiophenyl)-2(1H)-pyridinone (1.24 g) in dichloromethane (500 ml) was treated with m-chloroperbenzoic acid (85%, 0.92 g). After 2 hours the solution was washed with sodium bicarbonate-solution and evaporated to give the crude product (1.27 g, m.p. 239-241° C.). Purification by chromatography (silica, dichloromethane) followed by recrystallization from aqueous ethanol yielded the pure title compound, 0.81 g, m.p. 243-245° C.