Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[OH:19][N:20]=[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([OH:24])=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:19][N:20]=[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([OH:24])=[O:23]
Reactant: C1=COCCC1
Reactant: CC(C)CC(=NO)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)CC(=NOC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 87 %

Procedure:
9.6 Milliliters of 3,4-dihydro-2H-pyran and 0.29 g of p-TsOH.H2O were added to 50 ml of a solution of 4.35 g of α-hydroxyimino-isocaproic acid dissolved in dry CH2Cl2. The mixture was stirred for 100 minutes at room temperature. The reaction mixture was added to an aqueous solution saturated with NaHCO3 with ice cooling, and subjected to phase separation. An aqueous solution saturated with NaHCO3 was covered with ethyl acetate, then concentrated hydrochloric acid was added thereto, with stirring under ice cooling, to make the reaction mixture weakly acidic. The ethyl acetate layer was separated, washed with an aqueous selection saturated with NaCl, and dried over magnesium sulfate to obtain 6.00 g (87%) of the title compound as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:11][OH:12])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:11]=[O:12])[CH2:9][CH2:10]2)[CH:5]=[N:6][CH:7]=1
Reactant: OCC1(c2cncc(Br)c2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Product: O=CC1(c2cncc(Br)c2)CC1
Temperature: 25 °C

Procedure:
To a solution of the title compound from Example 73 Step A (114 mg, 0.500 mmol) in acetonitrile (2.5 mL) was added Dess-Martin Periodinane (254 mg, 0.600 mmol). The reaction stirred at room temperature until complete. It was then concentrated under reduced pressure, diluted with 2% methanol in dichloromethane, and passed through a syringe filter. Purification by flash chromatography on silica gel (20-100% ethyl acetate in hexanes) provided the title compound: LCMS m/z 227.86 [M+2+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5](Cl)[CH:6]2[CH:10]([N:11]=1)[N:9]([CH:12]1[CH2:16][CH:15]([OH:17])[CH:14]([CH2:18][O:19]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:13]1=[CH2:39])[CH:8]=[N:7]2.[OH-:41].[Na+]>C(#N)C>[NH2:2][C:3]1[NH:4][C:5](=[O:41])[C:6]2[N:7]=[CH:8][N:9]([CH:12]3[CH2:16][CH:15]([OH:17])[CH:14]([CH2:18][OH:19])[C:13]3=[CH2:39])[C:10]=2[N:11]=1
Reactant: [OH-]
Reactant: C=C1C(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(O)CC1N1C=NC2C(Cl)=NC(N)=NC21
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: C=C1C(CO)C(O)CC1n1cnc2c(=O)[nH]c(N)nc21
Temperature: 82 °C
Reaction time: 12 h
Yield: 73.1 %

Procedure:
Acetonitril (30 ml) and 2N aqueous hydrochloric acid (23.3 ml) were added to the compound of formula (VI) obtained in Example 1-8 (1.38 g, 2.56 mmol) and stirred at 82° C. for 12 hrs with heating. After completion of the reaction, the resulting mixture was cooled to room temperature and washed with ethyl acetate to remove tritylcarbinol. The material thus obtained was neutralized to pH 6.8 by using 3N aqueous sodium hydroxide (13.6 ml) and stirred at 90° C. for 1 hr. The solution thus obtained was stirred with cooling slowly to room temperature and further stirred at room temperature for 1 hr to obtain crystal. The resulting material was cooled to 6° C. and stirred for 1 hr to obtain the title compound (0.554 g, yield: 73.1%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:11][CH:10]=1)(C)(C)C.[ClH:31].CCOCC>CO>[ClH:31].[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:17]2[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)=[CH:13][CH:14]=1
Reactant: CN(C)c1nc(NCc2ccc(CNC(=O)OC(C)(C)C)cc2)nc2ccccc12
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CN(C)c1nc(NCc2ccc(CN)cc2)nc2ccccc12
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a cooled solution of {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-benzyl}-carbamic acid tert-butyl ester (3.90 g, 9.57 mmol) in MeOH was added 1 M HCl in Et2O (67.0 ml, 67.0 mmol) and the solution was stirred for overnight. The resulting mixture was concentrated to give N2-(4-aminomethyl-benzyl)-N4,N4-dimethyl-quinazoline-2,4-diamine hydrochloride as a white crystalline solid (3.48 g, 95.6%).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[CH3:12]O>>[ClH:1].[ClH:1].[CH3:12][O:10][C:9](=[O:11])[C@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][NH2:8])[NH2:2]
Reactant: CO
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H](N)CCCCN
Yield: 91.6 %

Procedure:
To a mixture of L-Lysine-Hydrochloride (100 g) in 1.75 L of methanol at 0° C. was bubbled dry HCl for 7 hours. The crude solid product was filtered, dried to get pure L-Lysine methyl ester dihydrochloride (117 g, 91.6%) as a white powder with a melting point of 204.5-206° C. The compound was characterized by 1H NMR (DMSO-d6) δ 1.48 (m, 2H, CH2), 1.68 (m, 2H, CH2), 1.90 (m, 2H, CH2), 2.80 (m, 2H, CH2), 3.78 (s, 3H, Ester), 4.00 (t, 1H, CH), 8.20 (bs, 2H, NH2), 8.70 (bs, 2H, NH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][CH:12]([S-:14])[CH3:13].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:14][CH:12]([CH3:13])[CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(C)[S-]
Reactant: N#Cc1cc(Cl)ccc1F
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc(Cl)cc1C#N
Yield: 88.9 %

Procedure:
(Step 1) A mixture of 5-chloro-2-fluorobenzonitrile (6.0 g) and sodium propane-2-thiolate (4.16 g) was stirred in N,N-dimethylformamide (30 ml) at room temperature for 18 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-chloro-2-[(1-methylethyl)sulfanyl]benzonitrile (7.26 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[Cl-:17].[Mn+2:18].[Cl-:19]>CO>[Cl:17][C:2]1([CH3:1])[CH2:16][NH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][N:3]1[Cl:19].[Mn+2:18]
Reactant: CC1CNCCNCCNCCNCCN1
Reactant: [Cl-]
Agent: [Mn+2]
Solvent: CO
Product: CC1(Cl)CNCCNCCNCCNCCN1Cl
Yield: 43 %

Procedure:
A solution of 2-methyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 2E (1.2 g, 5.3 mmole) and anhydrous manganese(II) chloride (0.67 g, 5.3 mmole) in anhydrous methanol (60 ml) was refluxed under a dry nitrogen atmosphere for 2 h. A small amount of suspended solid was removed by filtration and the solvent was removed in vacuo. The residue was recrystallized from ethanol-ethyl ether to give 0.81 g (43% yield) of the product as a white solid: FAB mass spectrum (NBA) m/z (relative intensity) 354 (M+, 3), 319/321 [(M-Cl)+, 100/31]; Anal. calcd. for C11H27Cl2MnN5 : C, 37.19; H, 7.66; Cl, 19.96; N, 19.72. Found: C, 36.73;H, 7.32; Cl, 19.85; N, 19.49.
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[OH:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([OH:30])([C:22]3=[O:29])[CH2:20]1)[CH2:26]2>>[C:1]([O:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][C:21]([OH:30])([C:22]3=[O:29])[CH2:20]1)[CH2:26]2)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Reactant: O=C1C2CC3CC(O)(C2)CC1(O)C3
Product: C=CC(=O)OC12CC3CC(C1)C(=O)C(O)(C3)C2
Yield: 87 %

Procedure:
The reaction was conducted in the same manner as said (2) except that 1,3-dihydroxyadamantane-4-one was used instead of the 1-hydroxyadamantane-2-one, and, as a result, a 1-acryloyloxy-3-hydroxyadamantane-4-one (yield: 87%, white solid) was produced.
Reaction SMILES: [C:1]1([C:7]23[CH2:15][C:14](=O)[CH2:13][N:8]2[C:9](=[O:12])[O:10][CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1B(O)O.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(Cl)(Cl)Cl.COCCOC>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:14]1[CH2:13][N:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]2([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: O=C1CN2C(=O)OCC2(c2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C1OCC2(c3ccccc3)C=C(c3cc(F)ccc3F)CN12
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
A suspension of 231 g (1.06 moles) of 1-6 in 11 L of THF in a 20 L jacketed reactor was stirred vigorously with overhead stirring for 1 h, then cooled to −70° C. To this suspension was added dropwise 1.28 L (1.28 moles) of a 1M solution of NaHMDS in THF. After stirring for 3 h, 478.9 g (1.28 moles) of solid N-phenylbis(trifluoro-methanesulphonimide) was added, followed by an additional 1.5 h of stirring, before being quenched by the addition of 2 L of a saturated aqueous NH4Cl solution. After the solution reached room temperature, 2 L of water and 2 L of EtOAc were added, the layers were separated, and the aqueous layer was extracted with 2 L of EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated by rotary evaporation. The residue was dissolved in 6 L of DME and 1.2 L of water in a 20 L jacketed reactor with overhead stirring, and the solution was degassed with a strong flow of N2 for 1 h. To the reactor was then added 201.6 g (1.28 moles) of 2,5-difluorophenylboronic acid, 134 g (3.19 moles) of LiCl, 338 g (3.19 moles) of Na2CO3, and 24.6 g (21 mmol) of tetrakis(triphenylphospine)palladium(O), and the reaction was heated at 90° C. for 2 h. Following this period of time, approximately 4.5 L of DME was distilled off, the remaining solution was cooled to room temperature, and dumped into 6 L of water and 8 L of CH2Cl2. The layers were separated, the aqueous layer was extracted with 2 L of CH2Cl2, the organic layers were combined, washed with 4 L of water, dried over Na2SO4 and concentrated by rotary evaporation to provide a dark red solid mass. This residue was swished with 500 mL of CHCl3, and filtered to provide a tan solid. The filtrate was concentrated to ˜300 mL and a second crop of solid was collected, combined with the first crop, and the combined material was swished with 500 mL of EtOAc overnight. This suspension was filtered to provide an off-white solid, the filtrate was concentrated to ˜250 mL and a second crop was collected, combined with the first crop, and the combined material (˜205 g) was recrystallized from 1.6 L of EtOAc to provide 1-7 as a white solid. Data for 1-7: 1HNMR (500 MHz, CDCl3) δ 7.5-7.3 (mn, 5H), 7.1-6.9 (m, 3H), 6.8 (s, 1H), 4.9 (d, 1H), 4.75 (d, 1H), 4.5 (d, 1H), 4.25 (d, 1H) ppm. HRMS (ES) calc'd M+H for C18H13F2NO2: 314.0987. Found: 314.0993.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]C(OCC)=O)[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.[CH3:24][Mg]Br.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C1COCC1.CCOCC.O.CCOC(C)=O>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:30]([CH3:29])([OH:32])[CH3:24])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1.[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:30]([OH:32])([CH3:29])[CH3:24])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Reactant: C[Mg]Br
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(O)CCN1CCC(c2nsc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
To a stirred solution, under N2, of ethyl 3-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]propionate (3.1 g, 9 mmol), in THF (100 ml) was added, dropwise, methylmagnesium bromide (9.0 ml, 27 mmol of a 3M solution in ether). The reaction was stirred at ambient temperature for 16 hours and then a saturated solution NH/4Cl was added dropwise, with cooling. The reaction was further diluted with H2O, and after extractive workup of the aqueous mixture with EtOAc, 2.8 g of a waxy solid resulted. The solid was dissolved in EtOAc and 3.0 g of fumaric acid was added, and 5.0 g of a fumarate salt was collected, which was contaminated with unreacted fumaric acid. The crude salt was recrystallized from MeOH--Et2O, and then from DMF to afford 1.6 g (45.7%) of the desired compound as a hemifumarate, m.p.=237°-239° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: COc1cccc(C(=O)CBr)c1
Product: CCOC(=O)n1c(C(=O)c2cccc(OC)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-methoxyacetophenone. 1H-NMR (CDCl3) δ: 8.25 (1H, d, J=1.5 Hz), 7.53 (1H, d, J=8.4 Hz), 7.36-7.26 (4H, m), 7.05-7.01 (1H, m), 5.78 (2H, s), 3.84 (3H, s), 3.78 (2H, q, J=7.0 Hz), 0.89 (3H, t, J=7.0 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=1)(=[O:3])[CH3:2].[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1.O>C(Cl)Cl.CN(C)C1C=CN=CC=1.Cl>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=1)[C:15]([CH:12]1[CH2:14][CH2:13]1)=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CC(=O)Nc1cccc(I)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)N(C(=O)C1CC1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
In analogy to Example 13ap), from N-benzyl-5-bromo-isatin (G.Tacconi et al., J. Prakt. Chem. 315, 339 (1973)) there is obtained the corresponding N-benzyl-5-bromo-isatin oxime as a yellow solid. Yield: 94%. Mass spectrum: peaks inter alia at 330 (M+, 17%); 285 (14%), 91 (100%). 13ar) 1.36 g of N-acetyl-3-iodo-aniline are dissolved in 25 ml of methylene chloride and treated with 61 mg of 4-dimethylamino-pyridine. A solution of 5.25 ml of cyclopropanecarbonyl chloride in 7 ml of methylene chloride is added dropwise to this solution. The mixture is stirred at room temperature overnight, then poured into 100 ml of water and made weakly acid with a few drops of dil. hydrochloric acid. Extraction with ethyl acetate and chromatography on silica gel with ethyl acetate gives 1.85 g of cyclopropanecarboxylic acid acetyl-(3-iodo-phenyl)-amide as a yellowish oil which solidifies in time. Yield: 92%. Mass spectrum: peaks inter alia at 329 (M+, 8%); 287 (58%), 69 (100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.[CH:18]1([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:28][C:27]2[CH:29]=[CH:30][C:24]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:25][CH:26]=2)=[CH:10][CH:9]=1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc(CNc2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.2 %

Procedure:
3-(4-Formylbenzoylamino)propionic acid methyl ester (10 g, 42.5 mmol) was dissolved in methanol (100 ml). With mechanical stirring 4-cyclohexylaniline (7.4 g, 42.5 mmol) was added in portions. Methanol (100 ml) was added and the resulting suspension was stirred under nitrogen at room temperature for 3 hours. Sodium cyano borohydride (4.01 g, 63.8 mmol) was added in portions and the resulting solution was stirred at room temperature for 4 days. Filtration and drying in vacuo of the formed crystals afforded 6.40 g (38%) of 3-{4-[(4-cyclohexylphenylamino)methyl]benzoylamino}propionic acid methyl ester as a solid. From the mother liquor a second crop of 2.49 g (15%) could be isolated by concentration in vacuo followed by washing with methanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[F:27].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CS(C)=O>[F:27][C:20]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[C:10]1[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=1[CH2:8][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CBr)c1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Piperidine (commercially available from Aldrich) (0.038 g, 0.44 mmol) was added to a solution of 66.63B (0.13 g, 0.37 mmol) in DMSO (3 mL). Cs2CO3 (0.18 g, 0.55 mmol) was then added to the reaction and it was stirred at room temperature for 1 hour. EtOAc (100 mL) was added and the organic phase was washed with water and brine and dried over anhydrous sodium sulfate. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:1 EtOAc/DCM) and gave 66.64A (100 mg) in 76% yield. MS ESI (pos.) m/e: 358 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23][OH:24])[CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH:23]=[O:24])[CH2:10][C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)n1ccc2ccccc21
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=CCC(CC(=O)n1ccc2ccccc21)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 22 %

Procedure:
A mixture of 1-[3-(3,4-dichlorophenyl)-5-hydroxy-1-oxopentyl]-1H-indole (4.25 g) and molecular sieves (4A, 2.75 g) in CH2Cl2 (40 mL) and was treated with TPAP (50 mg) and 4-methylmorpholine-N-oxide (2.75 mg) and stirred at room temperture for 2 hours. The reaction mixture was filtered through a pad of silica gel rinsed with EtOAc (100 mL) and concentrated under reduced pressure to yield an oil. Silica gel chromatography eluting with 50-75% EtOAc/Hexanes gave the desired title compound (930 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](#[N:14])[CH:12]=[CH2:13].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]2[O:10][CH2:13][CH:12]([C:11]#[N:14])[CH:5]([OH:6])[C:4]=2[CH:3]=1
Reactant: C=CC#N
Reactant: O=Cc1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CC1COc2ccc(Cl)cc2C1O
Reaction time: 8 h

Procedure:
To a stirred, refluxing mixture of 50 g of 3-chloro-6-hydroxybenzaldehyde and 62 ml of acrylonitrile in 50 ml of water was added dropwise over a three-hour period a solution of 12.8 g of sodium hydroxide in 120 ml of water. Then an additional 62 ml of acrylonitrile was added and the stirred mixture was refluxed for 2 hours, then allowed to stand at room temperature overnight. The crystals which formed were filtered off, washed with water and dried to give a solid, which was recrystallized from ethanol to give 6-chloro-3,4-dihydro-4-hydroxy-(2H)-1-benzopyran-3-carbonitrile (6A), a solid. A mixture of 6A with 250 ml of methanol containing 2 ml of sulfuric acid was refluxed for 4 days and stripped of solvent. The resulting residue was dry column chromatographed over silica gel, using Solvent No. 3 as eluent. The product obtained on workup was rechromatographed and recrystallized from ether to give methyl 6-chloro-2H-1-benzopyran-3-carboxylate (6B), as light yellow needles, mp: 106°-109° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:44](=[O:46])[CH3:45])[CH2:39][CH2:38]1>C(Cl)Cl.C(#N)C.O>[O:24]=[C:12]1[CH:13]=[C:14]([O:17][CH2:18][C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:16][N:11]1[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:37]2[CH2:42][CH2:41][CH:40]([NH:43][C:44](=[O:46])[CH3:45])[CH2:39][CH2:38]2)=[CH:4][CH:5]=1
Reactant: O=c1cc(OCc2cccs2)ccn1CCc1ccc(CO)cc1
Reactant: CC(=O)NC1CCNCC1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4cccs4)cc3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 45 mg (0.13 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(thiophen-2-ylmethoxy)-1H-pyridin-2-one (example 2.1a) in 3.0 mL DCM is added 55 μL triethylamine (0.40 mmol) and subsequently 20 μL (0.26 mmol) methanesulfonyl chloride at RT. The reaction mixture is stirred 1 h at RT and then 37 mg (0.40 mmol) N-piperidin-4-yl-acetamide is added. The mixture is stirred overnight at RT and is directly added to a reverse HPLC for purification (Zorbax stable bond, C18, 7 μm; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][NH:23][C:22](=[O:25])[C:21]=2[CH:26]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][N:23]=[C:22]([O:25][C@@H:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:1])([CH3:15])[C@H:3]3[OH:14])[C:21]=2[CH:26]=1
Reactant: O=c1[nH]oc2ccc(Cl)cc12
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Oc2noc3ccc(Cl)cc23)[C@@H]1O

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-chloro-benzo[d]isoxazol-3-one (prepared by literature known method) as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>C(O)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH3:16])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OC
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1OC
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A mixture of 500 mg (1.90 mmol) 4-chloro-7-ethoxy-6-methoxy-3-quinolinecarbonitrile, 20 ml ethanol, and 250 μl (2.28 mmol) 3-bromoaniline was heated to reflux under N2. At 3 hours, added 103 μl (0.95 mmol) and 10 ml ethanol and refluxed overnight. Removed heat and made basic with saturated sodium bicarbonate. Stripped solvent, slurried residue with hexane, collected solids, and dried. Washed with water and dried in vacuo, giving 554 mg of tan solid: mass spectrum (electrospray m/e): M+H=398, 399.8.