Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[C:5]2[C:20]([CH3:27])=[C:21]([OH:26])[C:22]([CH3:25])=[C:23]([CH3:24])[C:4]=2[O:3]1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][O:26][C:21]2[C:22]([CH3:25])=[C:23]([CH3:24])[C:4]3[O:3][C:2]([CH3:28])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][C:10]([N:13]5[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]5)=[CH:11][CH:12]=4)[C:5]=3[C:20]=2[CH3:27])=[CH:33][CH:32]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(N3CCN(C)CC3)cc1)C(C)(C)O2
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(N4CCN(C)CC4)cc2)C(C)(C)O3)cc1
Yield: 42 %

Procedure:
Using 2,2,4,6,7-pentamethyl-3-[4-(4-methyl-1-piperazinyl)phenyl]-2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride, the title compound was obtained in the same manner as In Example 1.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[Cu][C:22]#[N:23]>Cl.O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:23]
Reactant: Nc1ccc(C2CCCc3cncn32)cc1
Reactant: N#C[Cu]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(C2CCCc3cncn32)cc1
Temperature: 0 °C

Procedure:
A solution of 2.13 g of 5-(p-aminophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 4 ml of concentrated hydrochloric acid and 10 ml of water is added in an ice-bath and a solution of 0.78 g of sodium nitrite in 2 ml of water is added slowly. The solution is added via dropping funnel to an ice cooled solution of 3.0 g of copper(I) cyanide in 10 ml of water, keeping the temperature between 30°-40°. The reaction mixture is heated on a steam bath for 1 hr, cooled and brought to pH 9. The organic extracts are dried over sodium sulfate and evaporated and the residue is chromatographed on silica gel with ethyl acetate to yield the title compound.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[Na+].[Br:16][C:17]1[S:18][C:19](C2C=CC=CC=2)=[N:20][N:21]=1>CN(C)C=O>[Br:16][C:17]1[S:18][C:19]([O:13][CH2:12][CH:9]2[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)=[N:20][N:21]=1
Reactant: Brc1nnc(-c2ccccc2)s1
Reactant: CCCCCC1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC1CCC(COc2nnc(Br)s2)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 42.4 %

Procedure:
4-Pentylcyclohexylcarbinol (1.5 g, 8.15 mmol) are dissolved in dimethylformamide (40 ml), and sodium hydride (0.3 g, 12.23 mmol) is added at room temperature over a period of about 15 minutes. When the gas evolution is complete, 2-bromo-5-phenyl-1,3,4-thiadiazole (2.95 g, 12.23 mmol) is added to the resultant alkoxide, and the mixture is subsequently stirred at 50° C. for 6 hours, poured onto an ice/water mixture, filtered with suction and extracted. Separation by column chromatography (SiO2, CH2Cl2) gives 1.2 g (43% of theory) of 2-bromo-5-(4-pentylcyclohexylmethoxy)-1,3,4-thiadiazole.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH3:13])[CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:14][C:15]1([CH3:36])[CH:24]=[C:23]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[C:22]2[C:17](=[CH:18][C:19]([OH:35])=[CH:20][CH:21]=2)[O:16]1>>[CH2:2]([N:9]([CH2:10][CH2:11][O:35][C:19]1[CH:18]=[C:17]2[C:22]([C:23]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[CH:24][C:15]([CH3:36])([CH3:14])[O:16]2)=[CH:21][CH:20]=1)[CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(CCCl)Cc1ccccc1
Reactant: CC1(C)C=C(c2ccc3ccccc3c2)c2ccc(O)cc2O1
Agent: Cl
Product: CN(CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccc2ccccc2c1)Cc1ccccc1
Yield: 49 %

Procedure:
Reaction of N-benzyl-N-(2-chloroethyl)methylamine hydrochloride with 2,2-dimethyl-4-(2-naphthyl)-2H-chromen-7-ol by an analogous method to that described in Preparation 18 (c) gave the title compound (49%) as a colourless oil, The hydrochloride salt had m.p. 112°-115° C. decomposed.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:13])[CH2:9][CH2:10][C:11]#[CH:12].C(N(CC)CC)C>ClCCl.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>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:12]#[C:11][CH2:10][CH2:9][CH2:8][OH:13]
Reactant: Brc1ccccn1
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCCC#Cc1ccccn1
Yield: 54.7 %

Procedure:
As in Example 1, 15.8 g of 2-bromopyridine and 8.4 g of 4-pentyn-1-ol were reacted together in 125 mL of dichloromethane in the presence of 4.2 mL of triethylamine, 2.1 g of bis(triphenylphosphine)palladium dichloride and 0.135 g of cuprous iodide. After 48 hours at reflux, the reaction was worked up in the usual manner. Distillation of the crude product yielded 8.8 g of 5-(2-pyridinyl)-4-pentyn-1-ol (bp 115°-120° C./0.25 mm).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21].O1CCOCC1.C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (1.0 g), 2-(4-methanesulfonylbenzyl)-3-oxopentanoic acid methyl ester (1.4 g), polyphosphoric acid (5 mL) and dioxane (20 mL) was heated at 130° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and the pH adjusted to 4 by the addition of sodium acetate. The mixture was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a honey coloured gum, 2.3 g.
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:4][CH:3]1[CH2:5][OH:6].[H-].[Na+].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](F)[N:12]=1.O>O1CCOCC1.CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:6][CH2:5][CH:3]2[CH2:4][C:2]2([F:7])[F:1])[N:12]=1
Reactant: Fc1cccc(Br)n1
Reactant: OCC1CC1(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: FC1(F)CC1COc1cccc(Br)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To 307 mg (2.84 mmol) (2,2-difluorocyclopropyl)methanol in 1,4-dioxane (10 mL) is added 69 mg (2.84 mmol) sodium hydride and 500 mg (2.84 mmol) 2-bromo-6-fluoropyridine. The mixture is stirred for 2 h at 90° C. Water and DMF are added and the mixture is filtered and concentrated in vacuo. The residue is purified by HPLC (C18 RP Sunfire, acetonitrile/water (+0.1% TFA)) to yield the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:15][CH:14]=2)[C:3]1=[O:31].C1CCN2C(=NCCC2)CC1.[O:43]=O>>[CH3:1][N:2]1[C:3](=[O:31])[C:4]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:17][CH:18]=2)=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:6]1=[O:43]
Reactant: CN1CC(c2ccncc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Reactant: O=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN1C(=O)C(c2ccncc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Yield: 48 %

Procedure:
To a stirred solution of 1-methyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (200 mg, 0.49 mmol) in AcN (10 mL) was added DBU (224.5 mg, 1.47 mmol) dropwise and then the reaction mixture was stirred for 6 h under a continuous flow of oxygen. The reaction mixture was quenched with 1N HCl and extracted with EtOAc (2×20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to afford 1-methyl-3-(pyridin-4-yl)-4-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrole-2,5-dione (100 mg, 48%) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.18-8.09 (m, 1H), 8.0-7.95 (m, 3H), 7.65-7.59 (m, 3H), 7.48-7.39 (m, 1H), 7.28-7.18 (m, 4H), 7.1-7.09 (m, 2H), 5.25 (s, 2H), 2.86 (s, 3H); MS: M−H: m/z=420.1.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]([CH3:23])[CH:13]=3)[N:9]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:6]2=[N:7][CH:8]=1)[NH2:2].C(Cl)Cl.[CH:35](=O)[CH3:36].N>[Cu](Cl)Cl.CCOC(C)=O.CN(C=O)C>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:23])[CH:13]=[C:12]2[C:10]1[N:9]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:6]2[N:7]=[CH:8][C:3]3[N:4]([C:35]([CH3:36])=[N:2][N:1]=3)[C:5]=2[CH:11]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(NN)cnc3n1COCC[Si](C)(C)C)cn2C
Reactant: CC=O
Agent: Cl[Cu]Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4nnc(C)n43)n1COCC[Si](C)(C)C)cn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
To a round bottom flask were added 2-hydrazinyl-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.181 g, 0.413 mmol), DCM (5 mL) and acetaldehyde (10.0 M in DCM, 0.206 mL, 2.06 mmol). The reaction mixture was stirred at room temperature for about 1 h. The reaction mixture was concentrated under reduced pressure followed by the addition of DMF (8 mL) and copper(II) chloride (0.107 g, 0.796 mmol). The reaction mixture was heated to about 90° C. for about 15 min. The reaction mixture was cooled to room temperature and 10% aqueous ammonia (4.5 mL) and EtOAc (6 mL) were added. The reaction mixture was heated to about 40° C. for about 30 min. The reaction mixture was cooled to ambient temperature and extracted with EtOAc (50 mL). The organic layer was washed with water (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane to give 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazine (0.040 g, 21%): LC/MS (Table 1, Method d) Rt=1.67 min; MS m/z: 463 (M+H)+.
Reaction SMILES: ClC1C=CC(N[C:9](=[O:23])[C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[C:13]([O:15]CC)=[O:14])=CC=1.[OH-:24].[K+].[ClH:26]>CO>[Cl:26][C:10]1[CH:11]=[CH:12][C:18]([C:11]2[C:10]([C:9]([OH:23])=[O:24])=[C:20]([O:21][CH3:22])[CH:19]=[CH:18][C:12]=2[C:13]([OH:15])=[O:14])=[CH:19][CH:20]=1
Reactant: [OH-]
Reactant: Cl
Reactant: CCOC(=O)c1ccc(OC)c(C(=O)Nc2ccc(Cl)cc2)c1
Agent: [K+]
Solvent: CO
Product: COc1ccc(C(=O)O)c(-c2ccc(Cl)cc2)c1C(=O)O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Ethyl N-(4-chlorophenyl)-4-methoxyisophthalamate (11.8 g) obtained in step A was dissolved in 200 mL of methanol and 60-mL of a 20% aqueous solution of potassium hydroxide. The resulting solution was stirred for 30 minutes at 80° C., and then cooled to room temperature. One M hydrochloric acid was used to adjust the solution to pH of about 3. Then, the resulting precipitate was separated by filtration, washed with water, and dried over calcium chloride under reduced pressure, thereby obtaining 10.7 g (99%) of N=(4-chlorophenyl)-4-methoxyisophthalic acid.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C@@H:10]([CH:25]([CH3:27])[CH3:26])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[CH:25]([C@H:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:12][C:2](=[O:3])[NH:9]1)([CH3:27])[CH3:26]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)[C@H](N)C(O)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Trichloromethyl chloroformate (2.71 g, 13.7 mmol) was added to a mixture of (S)-2-amino-3-methyl-1,1-diphenyl-1-butanol (2) (3.18 g, 12.45 mmol) and triethylamine (2.68 g, 26.52 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 2 h at the same temperature and then poured into a brine solution (250 ml). The aqueous layer was made basic with NaOH pellets and organic products were extracted into AcOEt (5×200 ml). Combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The resulting crude product was washed with diethyl ether to obtain the title compound (3) (3.03 g, 86%) as a white solid. m.p. 250–251° C. (liti 250–251° C.). [α]D25=−201.59° (c, 0.0252 in DMSO). δH (DMSO-d6) 0.51 (3H, d, 3J=6.60 Hz, CH3), 0.92 (3H, d, 3J=7.20 Hz, CH3), 1.86 (1H, ds, 3J=2.10 and 6.60 Hz, CH—Me2), 4.46 (1H, d, 3J=6.5 Hz, CH—NH2), 7.24–7.72 (10H, m, Ar—H), 8.14 (1H, s, NH). δC 15.2 and 20.9 (CH3), 29.8 (CH), 64.9 (CH—NHCO), 88.4 (C—O), 125.8, 126.2, 127.9, 128.4, 128.8 and 129.1 (Ar), 140.5 and 146.1 (α-Ar), 158.1 (C═O). Ir 3295 (NH2), 1765 and 1745 (C═O). m/e (CI—NH3) 282 (MH+, 25%), 299 (MNH4+, 8%), 238 (96%), 223 (100%), 72 (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[SH:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:26][C:25](=O)[O:24][C:22](=[O:23])[CH2:21]2)=[CH:16][CH:15]=1>>[F:11][C:8]([F:9])([F:10])[C:6]1[CH:5]=[CH:4][C:3]2[S:12][C:25]([CH2:26][CH:20]([C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=3)[CH2:21][C:22]([OH:24])=[O:23])=[N:1][C:2]=2[CH:7]=1
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Product: O=C(O)CC(Cc1nc2cc(C(F)(F)F)ccc2s1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.55, starting from 2-amino-4-trifluoromethylthiophenol and 3-(4-chlorophenyl)glutaric anhydride, 4-(5-trifluoromethyl-2-benzothiazolyl)-3-(4-chlorophenyl)butanoic acid was obtained as colourless solid.
Reaction SMILES: C([C:4]1[NH:5][S:6](=[O:20])(=[O:19])[C:7]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([CH3:16])[C:8]=2[C:17]=1[OH:18])(=O)C>C(O)CO.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:16][N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:7]2[S:6](=[O:20])(=[O:19])[NH:5][CH2:4][C:17](=[O:18])[C:8]1=2
Reactant: CC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: OCCO
Product: Cn1c2c(c3ccccc31)S(=O)(=O)NCC2=O

Procedure:
The acetyl derivates of the formula XII are treated in the presence of an acid and under anhydrous conditions with ethyleneglycol and form the ketals of the formula ##STR13## wherein R2 and Y have the meanings defined above. For example, 3-acetyl-2,5-dihydro-4-hydroxy-5-methyl-1,2-thiazino[5,6-b]indole-1,1-dioxide is refluxed with ethyleneglycol in benzene as a solvent and in the presence of p-toluenesulfonic acid as a catalyst for 5 days, which yields the ethylene ketal of 2,5-dihydro-5-methyl-1,2-thiazino[5,6-b]indole-4(3H)-one-1,1-dioxide.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:45]=[CH:44][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:19]2=[O:43])=[CH:15][CH:14]=1.C(O)(=O)C.O>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:43])=[CH:44][CH:45]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc2cccnc21
Solvent: O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)cc2cccnc21
Yield: 96.5 %

Procedure:
A procedure similar to that described in Example 12 was repeated, except that the reaction was conducted using 270 mg of 5-[4-(1-methyl-7-azaindol-2-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 82) and 3 ml of a 2:1:3 by volume mixture of acetic acid, water and 1,4-dioxane. After the period allowed for the reaction had elapsed, the reaction mixture was freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 157 mg of the title compound, melting at 183°-185° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[C:5]([CH3:15])=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=O.[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH2:16][C:3]3[CH:4]=[C:5]([CH3:15])[C:6]([C:8]4[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=4)=[CH:7][C:2]=3[F:1])=[N:26][CH:25]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: Cc1cc(-c2cc(F)c(CC(=O)O)cc2C)ccn1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cc(C)c(-c4ccnc(C)c4)cc3F)nc2)CC1
Temperature: 25 °C

Procedure:
To a mixture of 2-(2-fluoro-5-methyl-4-(2-methylpyridin-4-yl)phenyl)acetic acid 191-6 (35 mg, 0.13 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (30 mg, 0.13 mmol) and HATU (50 mg, 0.13 mmol) in DMF (1.0 mL) was added DIEA (67 uL, 0.4 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was diluted into DMSO and purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2-fluoro-5-methyl-4-(2-methylpyridin-4-yl)phenyl)acetamide 191. MS m/z 462.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ10.51 (s, 1H), 8.49 (d, 1H), 8.03 (s, 1H), 7.91 (d, 1H), 7.43 (m, 1H), 7.32 (d, 1H), 7.28 (s, 1H), 7.21 (d, 1H), 7.08 (d, 1H), 3.77 (s, 2H), 3.53 (b, 4H), 3.14 (b, 2H), 3.07 (b, 2H), 2.55 (s, 3H), 2.20 (s, 3H), 2.04 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11]C)[CH:8]=2)[C:3]1=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCCC>[CH3:1][C:2]1([CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:15]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C(C)C)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC(C)C1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O

Procedure:
A stirred suspension of 2-methyl-2isopropyl-5-methoxy-6,7-dichloro-1-indanone (7.0 g., 0.0244 mole) and aluminum chloride (9.0 g., 0.068 mole) in heptane (400 ml.) is refluxed for one hour and cooled. The heptane is decanted from the reaction mixture and the solid residue is poiured into water (300 ml.) and concentrated hydrochloric acid (20 ml.). The crude product is extracted into ether (300 ml.), washed with water, dried over magnesium sulfate, distilled to a volume of 100 ml. and treated with hexane (100 ml.). The 2-methyl-2-isopropyl-5-hydroxy-6,7-dichloro-1-indanone which separates (6.5 g.) melts at 215° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.C([NH:40][C@H:41]([C:47]([OH:49])=[O:48])[CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])(OC(C)(C)C)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[NH2:40][C@@H:41]([CH2:42][CH2:43][CH2:44][CH2:45][NH:46][CH2:30][C:27]1[CH:26]=[N:25][C:24]([C:22]2[S:23][C:16]3[C:17](=[N:18][CH:19]=[CH:20][C:15]=3[O:14][C:11]3[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:6])=[CH:9][C:10]=3[F:32])[CH:21]=2)=[CH:29][CH:28]=1)[C:47]([OH:49])=[O:48]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)O
Reaction time: 1 h
Yield: 13.1 %

Procedure:
To a suspension of 321 (0.26 g, 0.58 mmol) and N-Boc-lysine (1.1 g, 4.6 mmol) in dichloromethane (75 mL) and was added acetic acid (0.066 mL, 1.2 mmol). The reaction mixture was stirred for 1 h, then sodium triacetoxyborohydride (0.37 g, 1.7 mmol) was added and the resulting mixture stirred for 18 h. The mixture was then partitioned between water and dichloromethane, and the solid precipitate removed by suction filtration through celite. The product was mostly in the solid filter cake, so this was solubilized by washing with 1:1 dichloromethane/methanol. This solution was concentrated and the residue was purified by Gilson reverse phase HPLC (35-75% MeOH/H2O, Aquasil C18, 30 min) and lyophilized to yield BOC-protected product. This was dissolved in dichloromethane (75 mL) and trifluoroacetic acid (3 mL), and stirred at r.t. for 3 h. The mixture was concentrated and the residue was purified by Gilson reverse phase HPLC (35-75% MeOH/H2O, Aquasil C18, 30 min) and lyophilized to yield title compound 324 (44 mg, 69% yield). 1H NMR (DMSO-d6) δ (ppm) 1H: 9.02 (s, 1H); 8.66 (s, 1H); 8.53 (d, J=5.3, 1H); 8.35 (s, 1H); 8.28 (d, j=8.4, 1H); 7.98 (d, J=6.3, 1H); 7.72 (dd, J=13.5, 2.3, 1H); 7.37 (t, J=9.0, 1H); 7.21 (d, J=10.0, 1H); 6.89 (s, 1H); 6.68 (d, J=5.3, 1H); 4.00 (s, 2H); 2.75-2.70 (m, 2H); 2.55-2.52 (m, 1H); 2.45 (m, 1H); 1.70-1.30 (m, 6H); 0.67-0.62 (m, 2H); 0.44-0.40 (m, 2H). LRMS: 579.5 (M+H).
Reaction SMILES: [OH: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.N1C=CC=CC=1.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[C:34]([O: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]([C:21]#[N:22])[CH:23]=4)[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4O)no2)cc1C#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4OC(=O)C(C)(C)C)no2)cc1C#N
Temperature: 25 °C
Reaction time: 96 h
Yield: 51.6 %

Procedure:
To a flask containing (R)-5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 5 (36 mg, 0.10 mmol) in DCM (1 mL) was added pyridine (24 μL, 0.3 mmol) and pivaloyl chloride (37 μL, 0.3 mmol). The reaction was stirred at room temperature for 4 days. The crude reaction mixture was washed with saturated sodium bicarbonate, dried over magnesium sulfate, and purified by chromatography (EA/hexane) to give 23 mg (52%) of (R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl pivalate 14 as a white solid. LCMS-ESI (m/z) calculated for C26H27N3O4: 445.2, tR=4.7 min. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=2.2, 1H), 8.28 (dd, J=8.9, 2.2, 1H), 8.12-8.05 (m, 1H), 7.46 (d, J=7.4, 1H), 7.34 (t, J=7.6, 1H), 7.06 (d, J=9.0, 1H), 6.19 (dd, J=7.3, 4.6, 1H), 4.73 (hept, J=6.1, 1H), 3.44 (ddd, J=17.5, 8.7, 5.4, 1H), 3.24 (ddd, J=17.5, 8.6, 5.7, 1H), 2.56 (tdd, J=8.6, 7.4, 5.4, 1H), 2.12-1.99 (m, 1H), 1.41 (d, J=6.1, 6H), 1.14 (s, 9H).