Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].COCCOC.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(O)C>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:31]3[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][C:32]=3[O:34][CH3:35])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3OC)c(F)ccc2c1N
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 63.5 %

Procedure:
A 2 L, 3-necked flask equipped with a mechanical stirrer was charged with 4-amino7-fluoro-8-iodo-N-propylcinnoline-3-carboxamide (40.5 g, 108.2 mmol), DME (700 mL, anhydrous), and ethanol (200 mL, absolute). A nitrogen dispersion tube was fitted into the suspension and the mixture was stirred until a solution was obtained. Water (300 mL) and PdCl2(PPh3)2 (7.6 g, 10mol %) were added. After 5 minutes, 2,4-dimethoxyphenyl boronic acid (39.4 g, 216.5 mmol) was added followed by cesium carbonate (70.3 g, 216.5 mmol). Nitrogen was bubbled through the suspension for 5 minutes. The mixture was heated to approximately 80° C. Additional 7:3:2 DME:H2O:EtOH (340 mL) was added as the reflux started. The reaction was refluxed 18 hours and then cooled to room temperature, diluted with ethyl acetate (1.5 L), and washed with water (3×500 mL). The aqueous layers were extracted with ethyl acetate (3×150 mL). The combined organic layers were stirred for 1 hour with 40 g of DARCO, dried over sodium sulfate, and filtered through Celite. The solids were washed with 5% methanol in chloroform (3×200 mL) and the filtrates concentrated to a dark semisolid. This was taken up in 200 mL 1% methanol in chloroform and warmed to solubilize the material. The solution was divided into two portions. Each portion was filtered through Whatman fluted filter paper onto a 330 g silica gel column and eluted with 5% ethyl acetate in dichloromethane. (Note: Some solid catalyst appeared to be removed via the filter paper.) The purest fractions from each column were combined in 5-10% ethyl acetate in dichloromethane. The solution was concentrated to approximately 200 mL, diluted with hexane (200 mL), and let stand at room temperature overnight. The resulting solids were isolated by filtration, washed with ether (3 times), and dried under vacuum at room temperature to afford the desired product (26.4 g, 63%). 1H NMR (500.333 MHz, CDCl3) δ 8.51 (bs, 1H), 7.86 (dd, J=9.4, 5.2 Hz, 1H), 7.50 (t, J=8.8 Hz, 1H), 7.27 (d, J=9.2, 1H), 6.66 (dd, J=8.2, 2.3 Hz, 1H), 6.63 (d, J=2.3 Hz, 1H), 3.87 (s, 3H), 3.71 (s, 3H), 3.44 (q, J=6.7 Hz, 2H), 1.64 (sextet, J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). MS APCI, m/z=385 (M+H). HPLC 2.61 min.
Reaction SMILES: [O:1]=[C:2]([C@H:23]([CH3:61])[C@@H:24]([O:52][C:53]([O:55][CH2:56][C:57]([Cl:60])([Cl:59])[Cl:58])=[O:54])[C@@H:25]([CH3:51])[CH2:26]/[CH:27]=[CH:28]/[C:29](/[CH3:50])=[CH:30]\[CH2:31][C@H:32]([O:42][Si](CC)(CC)CC)/[C:33](/[CH3:41])=[CH:34]/[C:35]1[N:36]=[C:37]([CH3:40])[S:38][CH:39]=1)[C:3]([CH3:22])([CH3:21])[C@@H:4]([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](CC)(CC)CC)(=O)=O.Cl.P([O-])([O-])([O-])=O>C(Cl)Cl.C(OCC)(=O)C>[O:1]=[C:2]([C@H:23]([CH3:61])[C@@H:24]([O:52][C:53]([O:55][CH2:56][C:57]([Cl:58])([Cl:59])[Cl:60])=[O:54])[C@@H:25]([CH3:51])[CH2:26]/[CH:27]=[CH:28]/[C:29](/[CH3:50])=[CH:30]\[CH2:31][C@H:32]([OH:42])/[C:33](/[CH3:41])=[CH:34]/[C:35]1[N:36]=[C:37]([CH3:40])[S:38][CH:39]=1)[C:3]([CH3:21])([CH3:22])[C@@H:4]([O:13][Si:14]([CH2:19][CH3:20])([CH2:15][CH3:16])[CH2:17][CH3:18])[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CC[Si](CC)(CC)O[C@@H](C/C=C(C)\C=C\C[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)OC(C)(C)C)O[Si](CC)(CC)CC)/C(C)=C/c1csc(C)n1
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@@H](CC(=O)O)C(C)(C)C(=O)[C@H](C)[C@@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C/C=C/C(C)=C\C[C@H](O)/C(C)=C/c1csc(C)n1
Reaction time: 10 h

Procedure:
A solution of tert-butyl (3S,6R,7S,8S,10E,12Z,15S,16E)-5-oxo-3,15-bis(triethylsilyloxy)-17-(2-methylthiazol-4-yl)-4,4,6,8,12,16-hexamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-heptadeca-10,12,16-trienoate (2.38 g) in 12 mL of CH2Cl2 is treated with 2,6-lutidine (0.86 mL) and triethylsilyl trifluoromethanesulfonate (0.98 g) at 0° C. for 30 minutes, then at ambient temperature for 10 hours. The mixture is diluted with 50 mL of ethyl acetate and poured into 20 mL of 1 N HCl. The organic phase is separated, washed with pH 7 phosphate buffer, dried with Na2SO4, filtered, and concentrated. The residue is dissolved in 5 mL of THF and treated with 0.5 mL of 0.1 N HCl in methanol. The reaction is monitored by thin-layer chromatography, with additional aliquots of methanolic HCl being added to achieve complete reaction. When complete, the reaction is poured into 15 mL of pH 7 phosphate buffer and extracted with ethyl acetate. The extract is washed with brine, dried with Na2SO4, filtered, and evaporated. The product is purified by flash chromatography on Sio2 (1:1 hexanes/ethyl acetate).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[CH:24][N:23]3[C:31]=2[CH3:32])[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)C1C=CC=CC=1.[H][H]>CN(C)C=O.[Pd]>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][CH2:19][C:20]2[N:21]=[C:22]3[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[CH:24][N:23]3[C:31]=2[CH3:32])=[CH:10][C:9]=1[OH:8]
Reactant: [H][H]
Reactant: CCOc1ccn2c(C)c(C=Cc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)nc2c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1
Yield: 62.8 %

Procedure:
A solution of 2-[2-(3-benzyloxy-4-nitrophenyl)vinyl]-7-ethoxy-3-methylimidazo[1,2-a]pyridine (3.8 g) in N,N-dimethylformamide (80 ml) was subjected to catalytic reduction over 10% palladium on carbon (1.9 g) under atmospheric pressure of hydrogen gas at 40° to 60° C. for hours. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with a mixture of diethyl ether and diisopropyl ether and the precipitate was collected by filtration to give 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-7-ethoxy-3-methylimidazo[1,2-a]pyridine (1.73 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25](=O)[C:26](OC)=[O:27].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]1[C:26](=[O:27])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(F)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5ccc(F)cc45)C(=O)NC3=O)c21
Temperature: 65 °C
Reaction time: 20 h
Yield: 42.2 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (350 mg, 1.86 mmol) and methyl 2-(5-fluoro-1H-indol-3-yl)oxoacetate (427 mg, 1.93 mmol) in DMF (25 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (6.5 mL, 6.5 mmol) at room temperature under N2. The reaction was heated to 65° C. and stirred for 20 h at this temperature. The reaction mixture was then cooled to room temperature and quenched with 1.0 N hydrochloric acid, extracted with EtOAc (50 mL), washed with H2O (2×30 mL), saturated NaCl (2×30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (282 mg, 42%) as a maroon solid, mp 230° C. dec. 1H NMR (DMSO-d6) δ 11.95 (bs, 1H), 11.18 (bs, 1H), 7.98 (s, 1H), 7.64 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 6.99 (m, 1H), 6.92 (m, 1H), 6.83 (m, 1H), 6.48 (m, 1H), 5.91 (m, 1H), 3.67 (s, 3H). MS (APCI): m/z=360 [C21H14FN3O2+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CCN=C=N[CH2:16][CH2:17][CH2:18]N(C)C.[CH:22](Cl)(Cl)Cl>C(O)(C)(C)C.CN(C1C=CN=CC=1)C>[C:17]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=1)([CH3:18])([CH3:22])[CH3:16]
Reactant: ClC(Cl)Cl
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cncc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1cncc(Br)c1
Temperature: 25 °C

Procedure:
5-Bromo-nicotinic acid (20.2 g, 100 mmol) was dissolved in CHCl3 (200 mL) and tert-BuOH (40 mL); and WSC (21.1 g, 110 mmol) and DMAP (21.1 g, 110 mmol) was added thereto in order, and stirred at room temperature over night. The reaction mixture was diluted with chloroform, washed with 0.5N HCl aq. (220 mL), 0.5N NaOH aq. (100 mL), brine and dried over MgSO4 and silica gel. After filtration, the solvents were removed in vacuo to afford 5-Bromo-nicotinic acid tert-butyl ester as a colorless solid. This solid was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=[O:13].[CH2:15]([O:17][C:18](=[O:34])[C:19]([CH2:31][CH2:32]O)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16]>CN(C)C1C=CN=CC=1>[CH2:23]([O:22][C:20](=[O:21])[C:19]([CH2:31][CH2:32][O:13][C:12](=[O:14])[CH2:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([O:17][CH2:15][CH3:16])=[O:34])[CH3:24]
Reactant: CCOC(=O)C(CCO)(C(=O)OCC)c1ccccc1
Reactant: Cc1c(CC(=O)O)cccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Product: CCOC(=O)C(CCOC(=O)Cc1cccc([N+](=O)[O-])c1C)(C(=O)OCC)c1ccccc1
Yield: 89.7 %

Procedure:
The 2-methyl-3-nitrophenylacetic acid (307 mg) obtained in Example 5c), 4-dimethylaminopyridine (217 mg) and the 2-(2-hydroxyethyl)-2-phenylmalonic acid diethyl ester (250 mg) obtained in Example 5e) were subjected to reactions similar to those in Example 1-3c) to give the title compound (366 mg).
Reaction SMILES: Br[CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1)=[N+:17]=[N-:18]
Reactant: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(N=[N+]=[N-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
A solution of 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (6.73 g, 25.29 mmoles), title B compound, in dry N,N-dimethylformamide (100 mL) was treated with sodium azide (3.79 g, 50.57 mmoles) and stirred at room temperature under argon for 4 hours. The reaction mixture was partitioned between 100 mL ethyl acetate and 200 mL distilled water. The organic layer was separated and the aqueous layer was extracted with 100 mL of ethyl acetate. The combined organics were washed successively with distilled water, saturated sodium bicarbonate solution, brine and dried over magnesium sulfate. The solvent was evaporated under vacuum to obtain an orange gum (5.62 g) which was triturated with pentane to provide the title compound (4.50 g, 78%) as an off-white solid, m.p. 63°-64° C. Microanalysis calculated for C12H12N4O: C, 63.15; H, 5.30; N, 24.55. Found: C, 63.57; H, 5.27; N, 24.75.
Reaction SMILES: N1CCCC1.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14](=[O:16])[CH3:15].[C:17]1([CH2:23][CH2:24][CH:25]=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH:25]([CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][C:14](=[O:16])[C:8]=2[CH:9]=1
Reactant: O=CCCc1ccccc1
Reactant: CC(=O)c1cc(F)ccc1O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: O=C1CC(CCc2ccccc2)Oc2ccc(F)cc21

Procedure:
Pyrrolidine (2.4 mL) was added to a solution of 2'-hydroxy-5'-fluoroacetophenone (15.1 g) and 3-phenylpropanal (13.2 mL) in toluene (30 mL), and the mixture heated under reflux in a Dean-Stark apparatus for 3 hours, cooled, diluted with ethyl acetate and washed with aqueous 1N HCl, aqueous 1N NaOH, H2O, brine, dried (Na2SO4), filtered and evaporated, and the residue purified by column chromatography (6:1 hexane/diethyl ether, SiO2) to yield 2,3-dihydro-6-fluoro-2-(2-phenylethyl)-4H-1-benzopyran-4-one (18 gm, Rf=0.3 4:1 hexane/diethyl ether).
Reaction SMILES: [N:1](C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21]C=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][CH2:57][N:58]1[CH2:62][CH2:61][CH2:60][C@H:59]1[C:63]([NH2:65])=[O:64]>C(Cl)Cl>[ClH:13].[C:63]([C@@H:59]1[CH2:60][CH2:61][CH2:62][N:58]1[CH2:57][CH2:56][CH2:55][O:31][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([NH:18][C:17]3[CH:32]=[CH:33][C:14]([Cl:13])=[CH:15][C:16]=3[F:34])=[N:1][CH:21]=[N:22]2)=[CH:27][C:26]=1[O:29][CH3:30])(=[O:64])[NH2:65]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1O
Reactant: NC(=O)[C@@H]1CCCN1CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCN1CCC[C@H]1C(N)=O
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinoline (128 mg, 0.4 mmol), (prepared as described for the starting material in Example 2), triphenylphosphine (314 mg, 1.2 mmol) and (S)-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (97 mg, 0.56 mmol), (prepared as described for the starting material in Example 50), in methylene chloride (4 ml). The mixture was stirred for 2 hours at ambient temperature, and further triphenylphosphine (105 mg, 0.4 mmol) and (S)-1-(3-hydroxypropyl)pyrrolidine-2-carboxamide (49 mg, 0.28 mmol) were added followed by the dropwise addition of diethyl azodicarboxylate (70 mg, 0.4 mmol). The mixture was stirred for 1 hour at ambient temperature, and was purified by pouring directly onto a silica column eluting with methylene chloride/acetonitrile/methanol (6/3/1 followed by 60/25/15). The purified oil was triturated with ether, collected by filtration, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride and 2M ethereal hydrogen chloride (0.5 ml) was added. The mixture was diluted with ether and the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give (S)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (70 mg, 32%).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:32](Cl)(=[O:36])[C:33](Cl)=[O:34].[CH2:38]([OH:40])[CH3:39]>>[CH2:38]([O:40][C:32](=[O:36])[C:33]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:28])([F:29])[F:27])=[CH:21][CH:20]=3)[CH:14]=2)[N:10]([CH2:9][C:8]2[CH:30]=[CH:31][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)[CH:11]=1)=[O:34])[CH3:39]
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(-c4ccc(OC(F)(F)F)cc4)ccc32)cc1
Reactant: CCO
Reactant: O=C(Cl)C(=O)Cl
Product: CCOC(=O)C(=O)c1cn(Cc2ccc(C(C)(C)C)cc2)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Yield: 59 %

Procedure:
Ethyl {1-[4-(tert-butyl)benzyl]-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate was prepared from 1-[4-(tert-butyl)benzyl]-5-[4-(trifluoromethoxy)phenyl]-1H-indole (2.52 g, 5.95 mmol), oxalyl chloride (1.6 mL, 18 mmol), and ethanol (5 mL) following the procedure described in Step 3 of Example 1. Purification by reverse phase HPLC using 92% acetonitrile and 8% water as the mobile phase followed by drying for 12 hours at 82° C. yielded the title compound as a light yellow solid (1.84 g, 59%), mp: 141-142° C. Mass spectrum (+ESI, [M+H]+) m/z 524; 1HNMR (500 MHz, DMSO-d6): δ 8.7 (s, 1H), 8.4 (d, 1H J=1.5 Hz), 7.75-8.0 (m, 3H), 7.6 (dd, 1H, J=8.6 Hz and 1.8 Hz), 7.45 (d, 2H, J=8.1 Hz), 7.35 (d, 2H, J=8.4 Hz), 7.25 (d, 2H, J=8.4 Hz), 5.6 (s, 2H), 4.35 (q, 2H, J=7.1 Hz), 1.35 (t, 3H, J=7.0 Hz), and 1.2 ppm (s, 9H). Elemental Analysis for C30H28F3NO4: Calculated: C, 68.82; H, 5.39; N, 2.68. Found: C, 68.84; H, 5.69; N, 2.57.
Reaction SMILES: C(OC(N1CC[C@@H](NC2C=CC(N3C[C@H](CNC(=O)C)OC3=O)=CC=2F)C1)=O)(C)(C)C.C([O:34][C:35]([C@H:37]1[C@@H:41]([CH2:42][NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][N:39]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:38]1)=[O:36])C.O.[OH-].[Li+].O>C1COCC1>[CH2:51]([N:39]1[CH2:40][C@H:41]([CH2:42][NH:43][C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[C@H:37]([C:35]([OH:36])=[O:34])[CH2:38]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CNC(=O)OC(C)(C)C
Agent: CC(=O)NC[C@H]1CN(c2ccc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(F)c2)C(=O)O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1CN(Cc2ccccc2)C[C@H]1C(=O)O
Temperature: 40 °C

Procedure:
To a solution of 2.9 (3R, 4R) and (3S, 4S)-1-benzyl-4-(tert-butoxycarbonylamino-methyl)-pyrrolidine-3-carboxylic acid ethyl ester (8.0 mmol) in 50 ml THF were added 671 mg lithium hydroxide mono hydrate (, 16 mmol) and 0.5 ml water. The solution was stirred at 40° C. and the reaction monitored by TLC. After 72 h the solvent was evaporated, the residue dissolved in dichloromethane, washed with water and brine, dried over Mg sulfate, filtered and evaporated. The residue was crystallized from a dichloromethane/hexane mixture.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[NH:7][N:8]=[C:9]2[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:21])=C([CH:20]=2)C#N)=[CH:4][CH:3]=1.[OH-:23].[K+].[CH2:25]([OH:27])[CH3:26]>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[NH:7][N:8]=[C:9]2[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:26]([CH:20]=2)[C:25]([OH:23])=[O:27])=[CH:4][CH:3]=1
Reactant: N#Cc1cc(Cc2n[nH]c(=O)c3ccc(Br)cc23)ccc1F
Reactant: CCO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccc(Br)cc23)ccc1F
Temperature: 100 °C
Yield: 79 %

Procedure:
5-((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorobenzonitrile (96) (2.4 g, 6.70 mmol) and potassium hydroxide (3.76 g, 67.01 mmol) were added to ethanol (20 mL) and water (80 mL) and heated at 100° C. for 5 hours. The ethanol was evaporated off and the aqueous was extracted with ethyl acetate (1×75 mL). The aqueous was then acidified to pH1 with conc HCl to afford a solid, which was filtered, washed with water and dried to the desired material as a beige solid. (2.000 g, 79% yield); 1H NMR (400.132 MHz, DMSO) δ 4.37 (2H, s), 7.26 (1H, t), 7.61-7.57 (1H, m), 7.83-7.82 (1H, m), 8.01 (1H, d), 8.18 (1H, d), 8.22 (1H, s), 12.67 (1H, s), 13.19 (1H, s); m/z (LC-MS, ESI+), RT=0.88 (M+H 376).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.Cl[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@@H:2]4[NH:1][S:31]([CH:30]=[CH2:29])(=[O:33])=[O:32])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4N)no2)cc1C#N
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Product: C=CS(=O)(=O)N[C@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a stirred solution of (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 50 (180 mg, 0.5 mmol) in DCM (2 mL) at 0° C. was added TEA (348 μL, 2.5 mmol) and 2-chloroethanesulfonyl chloride (245 mg, 1.5 mmol). The reaction mixture was warmed to room temperature and stirred for 30 min. Additional TEA (348 μL, 2.5 mmol) and 2-chloroethanesulfonyl chloride (245 mg, 1.5 mmol) were added and the reaction was stirred for 1 h. The solvent was removed and the product was purified by chromatography (EA/hexane) to give 144 mg (64%) of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide INT-14 as a white solid. LCMS-ESI (m/z) calculated for C23H22N4O4S: 450.1. found 473.1 [M+Na]+, tR=3.84 min. 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J=2.1 Hz, 1H), 8.27 (dd, J=8.9, 2.2 Hz, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.64 (dd, J=16.5, 9.9 Hz, 1H), 6.32 (d, J=16.5 Hz, 1H), 5.97 (d, J=9.9 Hz, 1H), 4.94-4.85 (m, 1H), 4.83 (d, J=9.1 Hz, 1H), 4.75 (hept, J=6.1 Hz, 1H), 3.42 (ddd, J=17.4, 8.8, 3.3 Hz, 1H), 3.17-3.01 (m, 1H), 2.63 (dtd, J=13.0, 8.0, 3.4 Hz, 1H), 1.99-1.86 (m, 1H), 1.44 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.20, 168.72, 162.89, 143.74, 142.71, 137.15, 134.16, 134.00, 128.91, 127.62, 127.15, 126.54, 123.38, 116.77, 115.38, 113.70, 103.96, 72.89, 58.59, 34.71, 31.56, 21.83. (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl) ethane sulfonamide was made in an analogous fashion from (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49.
Reaction SMILES: CS[C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[CH:9]=2)=[N:5][N:4]=1.Cl[C:26]1C=CC=C(C(OO)=O)C=1.[S:36]([O-:40])([O-])(=[O:38])=S.[Na+].[Na+]>CN(C)C(=O)C>[CH3:26][S:36]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=3)[CH:9]=2)=[N:5][N:4]=1)(=[O:40])=[O:38]
Reactant: CSc1nnc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)c2)o1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1nnc(-c2ccnc(Nc3cccc(C(F)(F)F)c3)c2)o1
Temperature: 50 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 4-[5-(methylthio)-1,3,4-oxadiazol-2-yl]-N-[3-(trifluoromethyl)phenyl]pyridin-2-amine (455 mg, 1.29 mmol) in N,N-dimethylacetamide (5 mL) was added m-chloroperbenzoic acid (70%, 619 mg, 2.58 mmol), and the resulting mixture was stirred at room temperature for 2 hr and at 50° C. overnight. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 15 min and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (126 mg, yield 25%) as yellow crystals.