Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH2:20][CH2:21]Br)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[K])(C)(C)C.O.C(OCC)(=O)C>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:21][CH2:20]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCBr)C1CCN(Cc2ccccc2)CC1
Agent: CC(C)(C)O[K]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(C2CCN(Cc3ccccc3)CC2)CC1
Yield: 73.2 %

Procedure:
13 ml of diisopropylamine was dissolved in a solvent mixture of tetrahydrofuran (140 ml) with HMPA (15 ml) in a nitrogen atmosphere and cooled to −78° C. Into the obtained solution was dropped 42 ml of a 2.5 M solution of n-butyllithium in hexane and the resulting mixture was stirred at 0° C. for 30 minutes. After cooling to −78° C. again, 15 ml of a solution of 5.8 g of ethyl (1-benzylpiperidin-4-yl)acetate in tetrahydrofuran was dropped thereinto. The reaction mixture was stirred at 0° C. for 1 hour. Then 1,2-dibromoethane was dropped thereinto at −78° C. again. The reaction mixture was stirred at 0° C. for 30 minutes and then brought back to room temperature. Next, it was distributed into water and ethyl acetate. The organic layer was extracted, washed with water and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.40 g of ethyl 2-(1-benzyl-4-piperidyl)-4-bromobutanoate as a colorless oily substance. A solution of 1.40 g of ethyl 2-(1-benzyl-4-piperidyl)-4-bromobutanoate in tetrahydrofuran (20 ml) was stirred at room temperature and 1.0 g of t-butoxypotassium was added thereto. The reaction mixture was distributed into water and ethyl acetate. The organic layer was extracted and washed with water. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 800 mg of the title compound as a colorless oily substance.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.O>CS(C)=O>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 25 °C

Procedure:
4-Fluorobenzonitrile (1 g, 8.26 mmol) and morpholine (2.2 mL, 25.2 mmol) were stirred in DMSO (25 mL) at 100° C. for 2.5 hours, cooled to room temperature, poured into H2O, and extracted with diethyl ether. The combined organic extracts were washed with H2O and brine, dried over Na2SO4, and evaporated in vacuo to provide the title compound.
Reaction SMILES: N1C=CC=[CH:2]1.[OH:6][C:7]1C2C(=CC=CC=2)C(O)=C[CH:8]=1.[OH:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([OH:29])=[CH:21][C:20]=1[C:30]1[N:34](C)[C:33]([CH2:36]C(OC)=O)=[CH:32][CH:31]=1>>[C:7]([C:32]1[C:31]([CH3:2])=[C:30]([C:20]2[C:19](=[O:18])[C:28]3[C:23]([C:22](=[O:29])[CH:21]=2)=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:34][C:33]=1[CH3:36])(=[O:6])[CH3:8]
Reactant: COC(=O)Cc1ccc(-c2cc(O)c3ccccc3c2O)n1C
Reactant: Oc1ccc(O)c2ccccc12
Reactant: c1cc[nH]c1
Product: CC(=O)c1c(C)[nH]c(C2=CC(=O)c3ccccc3C2=O)c1C

Procedure:
Among the pyrrole derivatives of 1,4-dihydroxynaphthalene which can be used according to the present invention, 2-(1-methyl-1H-pyrrol-2-yl)-[1,4]-dihydroxynaphthalene and methyl [5-(1,4-dihydroxynaphthalen-2-yl)-1-methyl-1H-pyrrol-2-yl]acetate are more particularly preferred.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Na+].CS[C:8]([S:22][CH3:23])=[CH:9][C:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=O)=[CH:14][CH:13]=1)=O.[C:24]([CH2:26][C:27]([NH2:29])=[O:28])#[N:25]>C(O)(C)C>[C:24]([C:26]1[C:27](=[O:28])[NH:29][C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:3][CH:2]([CH3:4])[CH3:1])=[O:18])=[CH:20][CH:21]=2)=[CH:9][C:8]=1[S:22][CH3:23])#[N:25]
Reactant: N#CCC(N)=O
Reactant: COC(=O)c1ccc(C(=O)C=C(SC)SC)cc1
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CSc1cc(-c2ccc(C(=O)OC(C)C)cc2)[nH]c(=O)c1C#N
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A 12% isopropanol suspension of sodium isopropoxide (9.08 g, 13.28 mmol) was added to a mixture of methyl 4-(3,3-bis(methylthio)acryloyl)benzoate (2.5 g, 8.85 mmol) and 2-cyanoacetamide (0.744 g, 8.85 mmol) in isopropanol (50 mL). The resultant mixture was heated to 100° C. for 3 h, cooled to room temperature and quenched with 0.3 N HCl (50 mL). The brown precipitate was collected by filtration, washed with water (10 mL) and dried under vacuum to give isopropyl 4-(5-cyano-4-(methylthio)-6-oxo-1,6-dihydropyridin-2-yl)benzoate (2.3 g, 63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.70-8.42 (4H, m), 6.67 (1H, br. s), 4.89-5.43 (1H, m), 1.10-1.64 (6H, m); MS (ES+) m/z: 329 (M+H); LC retention time: 3.18 min (analytical HPLC Method A).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:33]=[CH:34][C:35](F)=[C:36]([CH:40]=2)C(N)=O)=[CH:4][CH:3]=1.NC1N=C(C(NC(=O)CC2C3C(=CC=C(F)C=3)NC=2)CC2C=C(F)C=C(F)C=2)C(Br)=CC=1.[S:74](C1C=C(B(O)O)C=CC=1)(=[O:77])(=[O:76])[NH2:75]>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([S:74](=[O:77])(=[O:76])[NH2:75])[CH:40]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(-c2ccc(N)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)ccc1F
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Agent: Nc1ccc(Br)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1
Product: Nc1ccc(-c2cccc(S(N)(=O)=O)c2)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 1H of Example 1 utilizing 1G and (3-sulfamoylphenyl)boronic acid. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.03 (d, J=7.7 Hz, 1H), 7.96 (s, 2H), 7.91 (m, 1H), 7.57 (m, 3H), 7.24 (m, 1H), 6.92 (d, J=9.3 Hz, 2H), 6.70 (d, J=8.7 Hz, 1H), 6.54 (s, 1H), 6.20 (d, J=5.7 Hz, 2H), 5.54 (s, 2H), 5.33 (d, J=9.0 Hz, 1H), 3.63 (s, 2H), 2.99-2.85 (m, 2H). MS (m/z) 580.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:22][C@@H:23]1[CH2:28][C@@H:27]2[CH2:29][C@@H:25]([C:26]2([CH3:31])[CH3:30])[C@H:24]1[CH3:32].C(OCC)(=[O:35])C>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH2:21])=[O:35])[CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:22][C@@H:23]1[CH2:28][C@@H:27]2[CH2:29][C@@H:25]([C:26]2([CH3:31])[CH3:30])[C@H:24]1[CH3:32]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccnc(C#N)c3)c(=O)c1Br)C2(C)C
Reactant: CCOC(C)=O
Solvent: CCO
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccnc(C(N)=O)c3)c(=O)c1Br)C2(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
2-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(2-cyanopyridin-4-yl)methyl]acetamide (34.0 mg, 0.07 mmol) was dissolved in ethanol/30% aqueous potassium hydroxide (4 mL, 1:1) and stirred at 80° C. for 2 hours. After cooling, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol=8/1) to give the desired product.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:29])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([C:25](=[O:27])[CH3:26])[C@@H:9]([CH3:28])[CH2:8]1)[CH3:3].[N:30]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClCCl.CCCC(C)C>[C:25]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:33]4[CH2:34][CH2:35][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:32]4)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:29])[CH2:8][C@@H:9]1[CH3:28])(=[O:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCCC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C

Procedure:
1-methylethyl[(cis)-1-acetyl-6-(4-formylphenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 7) (95 mg, 0.241 mmol) was dissolved in Dichloromethane (DCM) (2 mL) and to this was added tert-butyl 1 piperazinecarboxylate (67.3 mg, 0.361 mmol) as a solid and the resulting solution stirred under nitrogen for 40 min. sodium triacetoxyborohydride (66.4 mg, 0.313 mmol) was added and stirred as a suspension over the weekend. The reaction was quenched with ammonium chloride (2 ml). The organics were separated and the aqueous reextracted with DCM (5 ml). The combined organics were washed with water (5 ml) and reduced in vacuo to give a colourless solid. (135 mg). The solid was dissolved in DCM and loaded onto a 12+M silica cartridge for automated flash chromatography. A gradient of 20 to 100% ethyl acetate in iso-hexane over 10 CV was used and the appropriate fractions reduced in vacuo to give a colourless oil which was dried on high vac overnight (98 mg).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30]Br)([CH3:25])([CH3:24])[CH3:23].[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:22]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][N:18]1[CH2:19][CH2:20][O:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:17]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Reactant: CC(C)(C)OC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1ccc(C2CN(CCCC(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
2-(4-Octyloxy-phenyl)-morpholine (1.50 g; 5.2 mmol), 4-bromo-butyric acid tert-butyl ester (1.38 g; 6.2 mmol) (prepared according to C. Morin, M. Vidal Tetrahedron, 1992, 48(42), 9277), potassium iodide (1.03 g; 6.2 mmol), K2CO3 (1.42 g; 10.29 mmol), and CH3CN (15 mL) were mixed and heated under reflux for 2 hours. After cooling to RT the reaction mixture was concentrated in vacuo, dissolved in EtOAc, washed with 5% aqueous NaHCO3 solution, dried (Na2SO4) concentrated in vacuo and purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 4-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-butyric acid tert-butyl ester (1.90 g), TLC (SiO2Rf. 0.20 EtOAc:hexanes 1:1)
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH:7](=[N:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCCN
Solvent: CO
Product: CCCCCN=Cc1ccccc1

Procedure:
100 g (1.15 mol) N-pentylamine was added to 200 ml methanol at a temperature of 22° C. 121.8 g (1.15 mol) benzaldehyde was added. The mixture was refluxed and subsequently, methanol was distilled off. The residual N-benzylidene-N-pentylamine 199.8 g (99.4%) was used in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C>ClCCl>[Si:21]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:14]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc(-c2ccc(CO)cc2OC)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2OC)cc1

Procedure:
A solution of Example 417A (136 mg, 0.50 mmol), tert-butyldimethylsilyl chloride (91 mg, 0.60 mmol), and N,N-diisopropylethylamine (129 mg, 1.0 mmol) in dichloromethane (5 mL) at room temperature was stirred for 3 hours, and filtered through a pad of silica gel. The pad was rinsed with ether and the combined solutions were concentrated to provide the desired product.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=CC(C2CCC2)=CC=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:3][CH2:2][CH2:13]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: Brc1ccc(C2CCC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(C2CCC2)cc1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 830 mg of 1-bromo-4-cyclobutyl-benzene (3.93 mmol), 2.7 ml of a 1.6 molar solution of n-BuLi in hexane (4.32 mmol) and 605 μl of DMF (7.86 mmol). The isolated residue was purified by flash column chromatography (5:95 EtOAc/cyclohexane) to give 422 mg of 4-cyclobutyl-benzaldehyde (67%) as a colorless liquid. 1H NMR (CDCl3, 300 MHz): δ 1.89 (m, 1H), 1.97-2.26 (m, 3H), 2.40 (m, 2H), 3.63 (quint, J=8.5 Hz, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H), 9.97 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](C1NC=CN=1)=[O:29])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl-].[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42][S:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][NH3+:64].CCN(CC)CC>CN(C=O)C>[N+:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][P:4]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:29])[NH:64][CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][S:43][S:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=2)(=[O:5])[O:3][CH2:1][CH3:2])=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: [NH3+]CCOCCOCCOCCCCCCCCCCCSSc1ccccn1
Reactant: CCOP(=O)(CCCCCCCCCCCOC(=O)c1ncc[nH]1)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCCCCCCCCCOC(=O)NCCOCCOCCOCCCCCCCCCCCSSc1ccccn1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 66 h

Procedure:
A solution of phosphonate 17 (68 mg, 0.14 mmol), amino disulfide 18 (60 mg, 0.13 mmol), and Et3N (35 mL, 0.25 mmol) dissolved in DMF was stirred at 60° C. for 66 h. After concentration of the reaction mixture, the crude residue was purified by column chromatography (hexane/EA=1:1) to afford the disulfide, which contained approximately 20% starting materials. ′H NMR (CDCl3, 500 MHz) δ 8.44 (s, 1H), 8.32 (s, 1H), 8.21 (d, J=9 Hz, 2H), 7.78 (br s, 1H), 7.70 (br s, 1H), 7.32 (d, J=9.0 Hz, 2H), 7.07 (br s, 1H), 4.15 (m, 2H), 3.98 (m, 2H), 3.62-3.49 (br m, 10H), 3.45 (m, 2H), 3.32 (m, 2H), 2.78 (t, J=7.5 Hz, 2H), 1.90 (m, 2H), 1.79 (m, 2H), 1.71-1.44 (br m, 4H), 1.40-1.07 (br, 33H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].C([Li])CCC.[Cl:15][C:16]1[CH:27]=[CH:26][C:19]([C:20](N(OC)C)=[O:21])=[CH:18][N:17]=1.[NH4+].[Cl-]>C1COCC1>[Cl:15][C:16]1[CH:27]=[CH:26][C:19]([C:20](=[O:21])[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=2[F:9])=[CH:18][N:17]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: Fc1cccc(Br)c1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)nc1)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a solution of 1-bromo-2,3-difluorobenzene (0.114 g, 0.746 mmol) in 3 ml of dry THF was added, at −78° C., n-butyl lithium (1.6 M in hexane, 0.47 ml, 0.749 mmol). The reaction mixture was stirred at this temperature for 1 hour. A solution of 6-chloro-N-methoxy-N-methyl-nicotinamide (0.13 g, 0.68 mmol) in 5 ml of THF was added and the reaction mixture was allowed to warm to RT and stir for 6 hours. Saturated NH4Cl was added and the mixture was extracted with CH2Cl2 (3×10 ml). The organic layers were combined, washed with brine, and dried over NaSO4. The solvents were removed in vacuo and the residue was purified by column chromatography (Hex/AcOEt 9:1) to give 130 mg (77%) of an oily product. IR, NMR.
Reaction SMILES: [ClH:1].[C:2]1([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:9]2=[O:24])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(Cl)Cl.C1COCC1>[ClH:1].[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:10]1([CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:24])[CH3:35]
Reactant: CCOC(=O)CCCBr
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CCCC1(Cc2ccncc2)C(=O)N(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,3-dihydro-1-phenyl-3-(4-pyridinylmethyl)-2H-indol-2-one hydrochloride (33.7 g, 0.1 mol) in 200 ml CH2Cl2 was treated with 150 ml 1N NaOH. The organic phase was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated to an oil which solidified on cooling. The "free base" was dissolved in 150 ml dry THF, cooled in an ice bath, treated with Nail (2.88 g, 0.12 mol), and stirred under dry nitrogen for 30 min. The mixture was treated with ethyl 4-bromobutyrate (19.5 g, 0.1 mol) in 25 ml dry THF. The mixture was stirred in the ice for 1 h and 16 h at room temperature. The reaction mixture was concentrated in vacuo, and the residue was partitioned between 300 ml Et2O and 200 ml water. The organic phase was washed with water and brine, dried over anhydrous MgSO4, filtered, treated with 150 ml 1N HCl-Et2O, and concentrated in vacuo. The residue was dissolved in 100 ml anhydrous EtOH with warming and stirred at room temperature for 24 h. The resulting crystals were collected by filtration, washed with a small portion of cold EtOH and Et2O, and dried in vacuo at 80° C. to give the desired product in 86% (38.6 g) yield; mp 182.5°-183.0° C.; IR(nujol): C=O @1722 and 1703 cm-1 ; NMR(DMSOd6TMS: δ1.15 (t, 3H, CH3), 1.2, 1.3 (2m, 2H, CH2CCCO), 2.1 (m, 2H, CH2CCO), 2.26 (t, 2H, CH2CO), [3.43 (d, 1H, J12), 3.64 (d, 1H, J12) CH2 -Pyr], 4.02 (q 2H, OCH2), [6.54 (m, 1H), 7.2 (m, 2 H), 7.5 (m, 5H), 7.68 (m, 1H) Ar--N-Phe], [7.10 (d, 2H), 8.70 (d, 2H) 4-Pyr]; Anal calcd for C26H26N2O3HCl, MW 450.97: C, 69.25; H, 6.04; N, 6.21. Found: C, 69.02; H, 5.98; N, 6.52. Mass spec m/e 415(M+1-HCl).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Br:9]Br.O>C(Cl)(Cl)Cl>[Br:9][C:5]1[S:4][C:3]([CH:7]=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1ccsc1C=O
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)sc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 3-methylthiophene-2-carbaldehyde (5.7 g) in chloroform (40 mL) was added dropwise bromine (2.5 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was and stirred at 0° C. for 30 min, and then at room temperature for 1 hr, and then under reflux overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (8.1 g, 88%) as a brown solid.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[OH:20])[CH:10]=[CH2:11].S(C1C=CC(C)=CC=1)(O[CH2:25][C@@H:26]1[O:28][CH2:27]1)(=O)=O>CN(C=O)C>[CH2:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[O:20][CH2:25][C@H:26]1[CH2:27][O:28]1)[CH:10]=[CH2:11]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: C=CCOc1ccc(Cl)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=CCOc1ccc(Cl)cc1OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To 4.0 g (79 mmole) of 60% sodium hydride/mineral oil dispersion in a one liter flask was added 300 ml of hexane. The mixture was swirled briefly, the solid allowed to settle and the supernatant liquid decanted. DMF (500 ml) was added, followed by a solution of 14.6 g (79 mmole) of 2-allyloxy-5-chlorophenol in 100 ml of DMF. The mixture was stirred at room temperature under nitrogen for 30 minutes, then 18.0 g (79 mmole) of (R)-glycidyl tosylate added. The mixture was heated under a nitrogen atmosphere at 80° C. for 24 hours. The solvent was evaporated in vacuum and replaced with 750 ml of methylene chloride. The solution was washed with 500 ml portions of 2 N HCl (aq), saturated aqueous sodium bicarbonate, saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum to give 20 g of a crude gum. This was column chromatographed on silica gel using methylene chloride as eluant to give 9.2 g of the title compound as a colorless oil. 1H (CDCl3) singlet, 6.93 δ (1 H); doublet, 6.90 δ (1 H); doublet, 6.80 δ (1 H);.multiplet, 6.05 δ (1 H); doublet, 5.40 δ (1 H); doublet, 5.25 δ (1 H); doublet, 4.55 δ (2 H); doublet of doublets, 4.25 δ (1 H); doublet of doublets, 3.97 δ (1 H); multiplet, 3.35 δ (1 H); triplet, 2.95 δ (2H); triplet, 2.75 δ (1 H).
Reaction SMILES: [C:1]([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14][CH3:15])[C:8]=2[C:7]([C:16]2[CH:17]=[C:18]([C:21]([OH:23])=O)[S:19][CH:20]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CC[N:26]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[C:1]([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14][CH3:15])[C:8]=2[C:7]([C:16]2[CH:17]=[C:18]([C:21]([NH2:26])=[O:23])[S:19][CH:20]=2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1nccc2c1c(-c1csc(C(=O)O)c1)nn2C(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 19518.3 %

Procedure:
To a solution of 4-(1-tert-butyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (1.50 g) in DMF (200 mL) were added EDCI hydrochloride (4.34 mg) and HOBt ammonium salt (3.44 g) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water at 0° C., and the white precipitate was collected by filtration. The obtained white solid was washed with water and saturated aqueous sodium hydrogencarbonate solution, and dried in vacuum to give the title compound (1.46 g).