Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][CH2:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:21]([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:21][N:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)Nc1cccc2c1NCCC2
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Product: CN1CCCc2cccc(NC(=O)OC(C)(C)C)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To a stirred solution of 8-(N-tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline (0.876 g, 3.52 mmol) in CH2Cl2 (35 mL), at room temperature was added excess methyl iodide (2 mL, 32.12 mmol). The mixture was stirred at room temperature for 48 hours. The mixture was poured into saturated aqueous NaHCO3 (25 mL) and diluted with CH2Cl2 (25 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by flash chromatography (36 g silica gel, 10:1 hexanes-ethyl acetate) provided 0.83 g (90%) of 1-methyl-8-(N-tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline as a colorless oil. 1H NMR (CDCl3) δ 1.53 (s, 9H), 1.84-1.92 (m, 2H), 2.62 (s, 3H), 2.79 (t, 2H, J=6.6 Hz), 3.03-3.07 (m, 2H), 6.73 (d, 1H, J=7.8 Hz), 6.95 (dd, 1H, J=7.8, 7.8 Hz), 7.18 (br s, 1H, NH), 7.82 (br d, 1H, J=7.8 Hz).
Reaction SMILES: C1C=CC2C(=O)[C:14]3[C:9](=[C:10]([OH:18])[CH:11]=[CH:12][C:13]=3[OH:17])C(=O)C=2C=1.[C:19]([O-])([O-])=[O:20].[K+].[K+]>C1C=CC=CC=1.[Ag]=O>[CH3:19][O:20][C:14]1[CH:9]=[C:10]([OH:18])[CH:11]=[CH:12][C:13]=1[OH:17]
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Reactant: O=C([O-])[O-]
Agent: O=[Ag]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc(O)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
A mixture of 1.00 g (7.10 mmol) of methoxyhydroquinone (3), 2.50 g (10.7 mmol) of silver oxide, and 1.20 g (8.50 mmol) of K2CO3 in 50 mL of benzene was stirred under argon at 25° C. for 3 h, the mixture was filtered through Celite, and washed with 5 mL of dichloromethane. The filtrate was concentrated to give 0.970 g (99% yield) of methoxybenzoquinone (6): 1H NMR d 6.72 (s, 2H), 5.95 (s, 1H), 3.84 (s, 3H). 13CNMR d 187.4, 181.6, 137.1, 134.4, 111.5, 107.6, 56.2. This material was used in the next step without purification.
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10](=S)[NH:9][C:8](=[S:14])[N:7]([CH2:15][CH3:16])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH2:17]([NH2:19])[CH3:18].C>O>[CH:1]1([C:4]2[NH:12][C:11]3[C:10]([NH:19][CH2:17][CH3:18])=[N:9][C:8](=[S:14])[N:7]([CH2:15][CH3:16])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCN
Reactant: CCn1c(=S)[nH]c(=S)c2[nH]c(C3CC3)nc21
Solvent: O
Product: CCNc1nc(=S)n(CC)c2nc(C3CC3)[nH]c12
Temperature: 150 °C

Procedure:
8-cyclopropyl-3-ethyl-2,6-dithioxanthine (20.19 g) prepared according to the method of example 2(i), and 70% ethylamine in water (320 ml 4.0M) were placed in a 450 ml pressure reactor and heated to 150° C. for 6 hours. The reaction solution was cooled to room temperature, treated with 2 portions of charcoal (0.2 g) filtered, and evaporated to dryness. The residue was triturated in menthol (300 ml), concentrated to about 200 ml, and the solid collected (16.48 g), mp 265° with decomposition.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].[CH2:13]([N:20]1[C:28]2[C:27](Cl)=[N:26][C:25]([NH2:30])=[N:24][C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN1C(=O)CCC1.O>[CH2:13]([N:20]1[C:28]2[C:27]([O:12][C:5]3[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=3[CH3:3])=[N:26][C:25]([NH2:30])=[N:24][C:23]=2[CH:22]=[CH:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: Nc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C)c(Oc2nc(N)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a stirred suspension of NaH (56 mg, 2.33 mmol) in dry NMP (2 mL) was added 2,4,6-trimethyl phenol (317 mg, 2.33 mmol). The mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (200 mg, 0.78 mmol) in dry NMP (1.5 mL) and the resulting solution was heated at 90° C. for 16 h. After completion of the reaction, the reaction mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, and brine and dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (3:1) to give the product as a white solid (140 mg, 50%).
Reaction SMILES: [H-].[Na+].[N+:3]([CH:6]=[C:7]1[NH:11][CH2:10][CH2:9][NH:8]1)([O-:5])=[O:4].[CH2:12](Br)[CH:13]=[CH2:14].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O>[N+:3]([CH:6]=[C:7]1[NH:11][CH2:10][CH2:9][N:8]1[CH2:14][CH:13]=[CH2:12])([O-:5])=[O:4]
Reactant: C=CCBr
Reactant: O=[N+]([O-])C=C1NCCN1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCNC1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 31.1 %

Procedure:
To 1.77 grams of a 57% by weight dispersion of sodium hydride in oil in 50 milliliters of dry dimethylformamide was added 5.16 grams of 2-(nitromethylene)imidazolidine. The mixture was cooled with an icebath, stirred and maintained under a nitrogen atmosphere. After 1.5 hours, 5.08 grams of allyl bromide was added. The mixture was stirred at about 10° for an additional hour, then allowed to warm to room temperature and poured into 400 milliliters of saturated aqueous sodium sulfate. The resulting mixture was extracted thrice with 300 milliliter portions of methylene chloride. The combined extract was dried (magnesium sulfate) and the solvent was evaporated. Addition of ether to the residue gave an oily red solid, which on recrystallization from chloroform (charcoal), gave 2.1 grams of 4 as tan crystals, melting point: 97°-98°.
Reaction SMILES: [CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:57]=[CH:56][C:29]([C:30]([NH:32][C@H:33]([C:41]([NH:43][C@H:44]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:31])=[CH:28][CH:27]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][Si](C(C)(C)C)(C)C)[CH:13]=2)[C@H:6]([CH3:58])[CH2:5]1)[CH:2]=[CH2:3].O.[F-].C([N+](CC)(CC)CC)C>C(#N)C>[CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:26]2[CH:57]=[CH:56][C:29]([C:30]([NH:32][C@H:33]([C:41]([NH:43][C@H:44]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:31])=[CH:28][CH:27]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[C@H:6]([CH3:58])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@@H](C)N([C@H](c2ccc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@@H]1C
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: C=CCN1C[C@@H](C)N([C@H](c2ccc(C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C)cc2)c2cccc(O)c2)C[C@@H]1C
Yield: 58 %

Procedure:
A portion of the benzhydrylpiperazine from above (0.36 g, 0.44 mmol) was stirred with tetraethylammonium fluoride hydrate (0.12 g, 0.67 mmol) in 10 mL of acetonitrile for 1 hr. The solvent was removed and the residue purified by chromatography on silica gel with dichloromethane:ethanol to give 0.180 g (58%) of tert-butyl N-(4-((αR*)-α-((2R*,5S*)-4-allyl-2,5-dimethyl -1-piperazinyl)-3-hydroxybenzyl)benzoyl)-L-phenylalanyl-L-leucinate as a white solid.
Reaction SMILES: [C:1](O)(=[O:5])[C:2]#[C:3][CH3:4].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[O:31]([C:38]1[CH:60]=[CH:59][C:41]([O:42][C:43]2[CH:48]=[CH:47][N:46]=[C:45]3[CH:49]=[C:50]([C:52]4[CH:53]=[C:54]([CH:56]=[CH:57][CH:58]=4)[NH2:55])[O:51][C:44]=23)=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCOCC1>[O:31]([C:38]1[CH:60]=[CH:59][C:41]([O:42][C:43]2[CH:48]=[CH:47][N:46]=[C:45]3[CH:49]=[C:50]([C:52]4[CH:53]=[C:54]([NH:55][C:1](=[O:5])[C:2]#[C:3][CH3:4])[CH:56]=[CH:57][CH:58]=4)[O:51][C:44]=23)=[CH:40][CH:39]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC#CC(=O)O
Reactant: Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC#CC(=O)Nc1cccc(-c2cc3nccc(Oc4ccc(Oc5ccccc5)cc4)c3o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a 20-mL glass vial was added but-2-ynoic acid (7.57 mg; 0.09 mmol), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (28.66 mg; 0.11 mmol), and N,N-diisopropylethylamine (0.05 ml; 0.30 mmol) suspended in dioxane (3.00 ml). The reaction mixture was stirred at room temperature for 1 hour. 3-[7-(4-phenoxyphenoxy)furo[3,2-b]pyridin-2-yl]aniline (29.60 mg; 0.08 mmol.) was added. The reaction mixture was then stirred at room temperature overnight. The mixture was purified using preparative HPLC to afford the title compound as a white solid (30.00 mg, 87%). HPLC (method F): 100%, RT=4.400 min. 1H NMR (DMSO-d6) δ [ppm] 10.79 (s, 1H), 8.40 (d, 1H), 8.24 (s, 1H), 7.70 (d, 1H), 7.66 (d, 1H), 7.62 (s, 1H), 7.47 (t, 1H), 7.41 (t, 2H), 7.38 (d, 2H), 7.16 (m, 3H), 7.08 (d, 2H), 6.77 (d, 1H), 2.05 (s, 3H). MS: m/z=461 [M+H]+, RT=4.52 min.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[Br:6][C:7]1[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[N:11][CH:12]=1>CC(O)=O.O1CCOCC1>[Br:6][C:7]1[CH:8]=[C:9]2[NH:14][C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:13][C:10]2=[N:11][CH:12]=1
Reactant: O=CC1CC1
Reactant: Nc1cc(Br)cnc1N
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Brc1cnc2nc(C3CC3)[nH]c2c1
Yield: 20.9 %

Procedure:
A solution of cyclopropanecarbaldehyde (0.89 g, 12.76 mmol, 1.2 eq), 5-bromopyridine-2,3-diamine x167 (2 g, 10.63 mmol, 1 eq) in AcOH (20 ml) and 1,4-dioxane (40 ml) is heated at 110° C. during 24 hours. After cooling, the solvents are evaporated under reduced pressure. The resulting brown solid is recrystallized in CH2Cl2/hexane (1/1) to yield 0.53 g of 6-bromo-2-cyclopropyl-1H-imidazo[4,5-b]pyridine x168 as an orange solid.
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)C([O:8][CH:9]([CH2:14][N:15]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[C:16](=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:10]([F:13])([F:12])[F:11])=O.N>CO>[F:34][C:30]1[CH:29]=[C:28]([N:15]([CH2:14][CH:9]([OH:8])[C:10]([F:11])([F:12])[F:13])[C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(OC(CN(C(=O)c1cccc(C(F)(F)F)c1)c1cccc(F)c1)C(F)(F)F)c1cccc(C(F)(F)F)c1
Agent: N
Solvent: CO
Product: O=C(c1cccc(C(F)(F)F)c1)N(CC(O)C(F)(F)F)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 60.9 %

Procedure:
A solution of 2,2,2-trifluoro-1-[[(3-fluorophenyl)[3-(trifluoromethyl)benzoyl]amino]-methyl]ethyl 3-trifluoromethyl-benzoate (600 mg, 1.06 mmol) from EX-662 in methanol was treated with 28% ammonia solution (122 μL). The solution was stirred at room temperature for 10 h. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine and water, then dried over anhydrous MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:8) to give 255 mg (61%) of the desired N-(3-fluorophenyl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-3-(trifluoromethyl)benzamide product as a white powder, 97% pure by HPLC analysis. 1H NMR (CDCl3) δ7.56 (m, 3H), 7.32 (m 2H), 6.98 (m, 1H), 6.90 (m, 2H), 4.49 (dd, 1H), 4.34 (d, 1H), 4.26 (m, 1H), 4.01 (dd, 1H). 19F NMR (CDCl3) δ−64.7 (s, 3F), −80.3 (s, 3F), −111.0 (m, 1F). HRMS calcd. for C17H12F7NO2: 396.0854 [M+H]+, found: 396.0821.
Reaction SMILES: Cl[C:2]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH:4]=O.[C:22]([OH:26])(=[O:25])[CH2:23][SH:24].C(N(CC)CC)C>N1C=CC=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:2]2[S:24][C:23]([C:22]([OH:26])=[O:25])=[CH:4][C:3]=2[C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[CH:16][CH:17]=1
Reactant: O=CC(=C(Cl)c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)CS
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(-c2ccc([N+](=O)[O-])cc2)c(-c2ccc(F)cc2)s1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 3-chloro-3-(4-fluorophenyl)-2-(4-nitrophenyl)propenal (1.5 g), thioglycolic acid (0.36 ml) and triethylamine (1.5 ml) in pyridine (7.6 ml) was stirred at 70° C. for 1 hour and refluxed for 7 hours. Pyridine was evaporated, and the residue was dissolved in ethyl acetate, washed with water and dilute hydrochloric acid, dried and concentrated. The residue (1.6 g) was washed with toluene to give pale brown crystals of 5-(4-fluorophenyl)-4-(4-nitrophenyl)thiophene-2-carboxylic acid (1.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[C:22](=[O:25])(O)[O-:23].[Na+]>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([NH:20][C:22](=[O:25])[O:23][C:4]([CH3:15])([CH3:5])[CH3:3])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=NC2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.770 g, 1.624 mmol; prepared as described in Method BB26) was dissolved in dioxane (8 mL). 8 mL of saturated sodium bicarbonate solution was added, followed by boc-anhydride (3.77 mL, 16.24 mmol). The reaction was stirred overnight at RT. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via silica gel chromatography (gradient elution 0-25% EtOAc:Hex) to afford tert-butyl 3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate as a yellow solid. MS m/z=576.0. Calc'd for C19H17BrIN3O3S: 574.23.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]2[C:15]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[N:16][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:18][CH:19]=2)[CH:5]=[C:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[O:8][CH3:9].CC1(C)C(C)(C)OB([C:38]2[CH:39]=[C:40]3[C:44](=[CH:45][CH:46]=2)[C:43](=[O:47])[CH2:42][CH2:41]3)O1>>[C:10]([C:6]1[C:7]([O:8][CH3:9])=[C:2]([C:38]2[CH:39]=[C:40]3[C:44](=[CH:45][CH:46]=2)[C:43](=[O:47])[CH2:42][CH2:41]3)[CH:3]=[C:4]([C:14]2[C:15]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[N:16][C:17]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[N:18][CH:19]=2)[CH:5]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3=O)OC1(C)C
Reactant: COc1c(Br)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C
Product: COc1c(-c2ccc3c(c2)CCC3=O)cc(-c2cnc(OC(C)(C)C)nc2OC(C)(C)C)cc1C(C)(C)C

Procedure:
A solution of Example 2 Part A (0.150 g, 0.32 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one (0.092 g, 0.36 mmol) were reacted in the same manner as Example 50 Part A using 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex as catalyst at 100° C. for 1.5 hours in the microwave and for 4 hours at 100° C. in an oil bath to give crude product which was purified by silica gel flash chromatography eluting with ethyl acetate/hexane (0% to 15%) to give the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Yield: 41.1 %

Procedure:
To a solution of 3-acetylamino-2-benzoyl-6-chloro-1-(ethoxycarbonyl)indole (556 mg, 1.4 mmol) in ethanol/water (3:1, 20 ml) was added KOH (85% pellets, 480 mg, 7.2 mmol) and the mixture was heated at reflux temperature for 1 h. The mixture was cooled and concentrated, and the residue partitioned between water (50 ml) and diethyl ether (100 ml). The organic extract was washed with water (100 ml) and then brine (100 ml). After drying (MgSO4) and removal of solvent, the crude product was recrystallized from dichloromethane/hexane to afford 180 mg (41%) of the title compound as a yellow powder. m.p.: 212-213° C. 1H-NMR (CDCl3) δ: 9.90 (1H, br s), 8.29-8.15 (2H, m), 7.84-7.75 (2H, m), 7.70-7.52 (3H, m), 7.32-7.27 (1H, m), 7.12 (1H, dd, J=1.83, 9.16 Hz), 2.26 (3H, s). IR (KBr) ν: 3400, 1680, 1640, 1520, 1320 cm−1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][C:18]3[NH:17][C:16]([CH3:21])=[CH:15][C:14]=3[C:13]=2[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[N:4]=1.S1(CCCC1)(=O)=O.F[B-](F)(F)F.[O:40]=[N+:41]=[O:42].N>C(#N)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][C:18]3[NH:17][C:16]([CH3:21])=[C:15]([N+:41]([O-:42])=[O:40])[C:14]=3[C:13]=2[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[N:6]=1
Reactant: O=[N+]=O
Reactant: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2[nH]c(C)cc12
Agent: F[B-](F)(F)F
Agent: N
Solvent: CC#N
Solvent: O=S1(=O)CCCC1
Product: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2[nH]c(C)c([N+](=O)[O-])c12
Temperature: -30 °C
Reaction time: 5 h
Yield: 55 %

Procedure:
2.0 g of allyl 5-[(4,6-dimethoxypyrimidin-2-yl)oxy]-2-methylindol-4-carboxylate was dissolved in 25 ml of acetonitrile, and the solution was cooled to -30° C. 16.3 ml of a 0.5M sulfolane solution of nitronium tetrafluoroborate was dropwise added thereto, and the mixture was stirred for 5 hours. After adding 2 ml of aqueous ammonia, the mixture was returned to room temperature and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. Crystals obtained by concentration under reduced pressure, were washed with hexane to obtain 1.23 g (yield: 55%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([C:21]3[O:22][C:23]([CH3:26])=[N:24][N:25]=3)[CH:18]=[CH:17][C:16]=2[CH3:27])=[CH:11][CH:10]=1)=[O:8].I[CH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]([CH3:32])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([C:21]3[O:22][C:23]([CH3:26])=[N:24][N:25]=3)[CH:18]=[CH:17][C:16]=2[CH3:27])=[CH:11][CH:10]=1)=[O:8]
Reactant: CI
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc(Cl)c4)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4cccc(Cl)c4)cc3)c2)o1

Procedure:
N-(3-Chlorobenzyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(3-chlorobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.76,(1H, b), 7.59-7.33,(8H, m), 7.23,(1H, b), 4.70-4.55,(2H, m), 2.92,(3H, s), 2.55,(3H, s), 2.32,(3H, s). LCMS; retention time 3.58 min, MH+ 432/434.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[O:19][C:18]([C:20]([O-:22])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[CH3:24][C:25]([NH2:28])([CH3:27])[CH3:26].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[C:25]([NH:28][C:20]([C:18]1[O:19][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]2)=[CH:16][CH:17]=1)=[O:22])([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)[O-])o2)CC1
Reactant: CC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)o1
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of sodium 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)furan-2-carboxylate (4.558 g, 13.72 mmol), 2-methylpropan-2-amine (1.003 g, 13.72 mmol, 1.441 mL) and triethylamine (4.16 g, 41.1 mmol, 5.72 mL) in dichloromethane was added 1-propanephosphonic acid cyclic anhydride (17.46 g, 27.4 mmol, 16.33 mL, 50% solution in ethyl acetate). The reaction was stirred for 2 hours then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with sodium bicarbonate, water and brine. The organic phase was concentrated under reduced pressure to give the title compound (2.4 g). MS (ESI) m/z 366.3 [M+H]+
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C([O-])([O-])=O.[K+].[K+].Cl.[NH:22]=[C:23]1[NH:28][CH2:27][CH:26]([OH:29])[CH2:25][NH:24]1>CCO>[OH:29][CH:26]1[CH2:27][N:28]2[C:4](=[O:14])[CH:5]=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:22]=[C:23]2[NH:24][CH2:25]1
Reactant: N=C1NCC(O)CN1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccccc2)nc2n1CC(O)CN2
Temperature: 90 °C
Reaction time: 17 h

Procedure:
In a 250 mL RBF with a stirrer bar, a mixture of 3-oxo-3-phenyl-propionic acid ethyl ester (15 g, 78 mmol), K2CO3 (11.0 g, 80 mmol) and 2-imino-hexahydro-pyrimidin-5-ol hydrochloride (11.8 g, 78 mmol) in EtOH (150 mL) was heated at 90° C. under nitrogen overnight. After 17 h, the mixture was cooled to room temperature, and filtered. The mother liquid was concentrated to a sludge that was then diluted with H2O. The resulting slurry was filtered and the solid was washed first with MeOH, then a mixture of EtOAc-MeOH (2:1) to give the first batch of product. The solid residue from the crude reaction was washed first with H2O (3×10 mL), then MeOH, and finally a mixture of EtOAc-MeOH (2: 1) to yield a second batch of product. The combined products were the dried in air to provide a white solid. 1H NMR (400 MHz, DMSO6): 7.94 (m, 2 H), 7.44 (bt, J 3.2, 0.5 H), 6.10 (s, 1H), 5.35 (d, J 3.2, 0.5 H), 4.22 (m, 1 H), 4.12 (d, J 14,1H), 3.54 (dd, J 14, 2.0,1 H), 3.39 (d, 12.4, 1H), 3.18 (m, 1H). M+1: 244.
Reaction SMILES: [O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N:5]=[C:4]([CH2:15][CH2:16][CH2:17][OH:18])[N:3]=1)[CH2:12][CH2:11][CH2:10]3.CO.CC[O:23]C(C)=O>>[O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N+:5]([O-:23])=[C:4]([CH2:15][CH2:16][CH2:17][OH:18])[N:3]=1)[CH2:12][CH2:11][CH2:10]3
Reactant: [O-][n+]1nc(CCCO)nc2cc3c(cc21)CCC3
Reactant: CCOC(C)=O
Solvent: CO
Product: [O-][n+]1nc(CCCO)[n+]([O-])c2cc3c(cc21)CCC3

Procedure:
H2O2 (70%, 1.6 mL, ca. 33 mmol) was added dropwise to a stirred solution of TFAA (4.6 mL, 33 mmol) in DCM (30 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. The solution was added to a solution of 1-oxide 70 (0.86 g, 3.3 mmol) in DCM (50 mL) at 0° C. and the solution was stirred at 20° C. for 16 h. Dilute aqueous NH3 solution (30 mL) was added and the mixture stirred vigorously for 30 min and then extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give (i) starting material 70 (283 mg, 33%) and (ii) 1,4-dioxide 71 (347 mg, 40%) as a yellow solid: mp (MeOH/EtOAc) 153-155° C.; 1H NMR δ 8.33 (s, 1H, H-9), 8.26 (s, 1H, H-5), 3.68 (br dt, J=6.1, 5.7 Hz, 2H, CH2O), 3.33 (t, J=6.9 Hz, 2H, CH2), 3.13-3.20 (m, 4H, H-6, H-8), 3.09 (br t, J=6.1 Hz, 1H, OH), 2.26 (p, J=7.5 Hz, 2H, H-7), 2.10-2.18 (m, 2H, CH2); 13C NMR δ 155.5, 155.0, 150.9, 138.8, 134.0, 115.8, 114.1, 61.2, 33.4, 32.9, 29.6, 26.8, 25.6. Anal. calcd for C13H15N3O3: C, 59.8; H, 5.8; N, 16.1. Found: C, 60.0; H, 5.7; N, 16.1%.