Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:18]([N:8]1[CH2:9][CH:10]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH:6]([CH2:4][OH:3])[CH2:7]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3SR,4RS) 1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (CAS RN: 80896-63-5) (30 g, 0.087 mol) were dissolved in THF (400 mL). At 0° C. LiAlH4 (3.5 g, 0.092 mol) was added portion wise. After stirring at 0° C. for 4 h water (18 mL), then 5N NaOH (18 mL) and additional water (54 mL) was added. After stirring at ambient temperature for 1 h the mixture was extracted with ethyl acetate (3×100 mL), the combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude title product was obtained as a white solid (24.6 g, 93%) and directly used in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.I[C:26]1[CH:39]=[N:38][C:29]2[NH:30][C:31]3[CH:36]=[N:35][C:34]([Br:37])=[CH:33][C:32]=3[C:28]=2[CH:27]=1>[F-].[K+].C(#N)C.C(OCC)(=O)C>[Br:37][C:34]1[N:35]=[CH:36][C:31]2[NH:30][C:29]3[N:38]=[CH:39][C:26]([C:12]4[CH:11]=[CH:10][C:9]([CH2:8][N:5]5[CH2:4][CH2:3][C:2]([CH3:1])([CH3:24])[CH2:7][CH2:6]5)=[CH:14][CH:13]=4)=[CH:27][C:28]=3[C:32]=2[CH:33]=1
Reactant: CC1(C)CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Temperature: 80 °C
Yield: 32.5 %

Procedure:
A degassed mixture of 4,4-dimethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]piperidine (836 mg, 2.5 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (500 mg, 1.3 mmol), 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (109 mg, 0.13 mmol) in 1N aqueous potassium fluoride solution (25 mL) and acetonitrile (25 mL) was heated at 80° C. for 18 h. The cooled reaction mixture was diluted with ethyl acetate (100 mL) then washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 120 g column, ISCO, 0-15% methanol in DCM) to afford the title compound as an off-white solid (190 mg, 33%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.85 (d, J=2.2 Hz, 1H), 8.76 (d, J=2.2 Hz, 1H), 8.70 (d, J=0.9 Hz, 1H), 8.32 (d, J=0.9 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 3.82 (s, 2H), 2.77-2.63 (m, 4H), 1.52 (t, J=5.6 Hz, 4H), 1.00 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: NCc1ccc(F)cc1
Product: CCCN(CC(=O)NCc1ccc(F)cc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-propylglycine and 4-fluorobenzyl amine: MS (APCI) m/z 394 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](Cl)=[N:18][CH:19]=[N:20]3)=[C:15]([O:24][CH:25]([CH3:27])[CH3:26])[CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[O:35][CH2:36][O:37][C:30]=12>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([NH:28][C:29]4[CH:34]=[CH:33][N:32]=[C:31]5[O:35][CH2:36][O:37][C:30]=45)=[N:18][CH:19]=[N:20]3)=[C:15]([O:24][CH:25]([CH3:27])[CH3:26])[CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(CCOc2cc(OC(C)C)c3c(Cl)ncnc3c2)CC1
Reactant: Nc1ccnc2c1OCO2
Product: CC(=O)N1CCN(CCOc2cc(OC(C)C)c3c(Nc4ccnc5c4OCO5)ncnc3c2)CC1
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 16, 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-chloro-5-isopropoxyquinazoline was reacted with 4-amino-2,3-methylenedioxypyridine to give the title compound in 55% yield; NMR Spectrum: (CDCl3) 1.55 (s, 3H), 1.56 (s, 3H), 2.1 (s, 3H), 2.59 (m, 4H), 2.89 (m, 2H), 3.51 (m, 2H), 3.67 (m, 2H), 4.24 (m, 2H), 4.85 (m, 1H), 6.13 (s, 2H), 6.57 (s, 1H), 6.85 (s, 1H), 7.71 (d, 1H), 8.41 (d, 1H), 8.66 (s, 1H); Mass Spectrum: M+H+ 495.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]2[N:14]=[C:15]([Cl:19])[N:16]=[C:17](Cl)[C:12]=2[N:11]=[C:10]([Cl:20])[N:9]=1.O>C1COCC1>[Cl:20][C:10]1[N:9]=[C:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:13]2[N:14]=[C:15]([Cl:19])[N:16]=[C:17]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:12]=2[N:11]=1
Reactant: Clc1nc(Cl)c2nc(Cl)nc(Cl)c2n1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: Clc1nc(N2CCCCC2)c2nc(Cl)nc(N3CCCCC3)c2n1
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
Piperidine (0.8 ml, 8 mmol) was added to tetrachloropyrimidopyrimidine (0.54 g, 2 mmol) in THF (15 ml) and the resulting solution was stirred for 10 minutes until a yellow precipitate formed. Water (75 ml) was added and the mixture stirred for a further 10 minutes. The precipitate was filtered under suction, washed with water and dried in vacuo (P2O5) yielding the title compound as a yellow powder (0.62 g, 75%), m.p. 240-241° C., δH (CDCl3, 200 MHz) 1.81 (12H, s, 2×(CH2)3), 4.15 (8H, s br, 2×N(CH2)2); m/z (El) 366 (M+−1), 198.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[Sn](Cl)Cl.Cl.[OH-].[Na+]>C(O)C.ClCCl>[Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Nc1ccc2nc(Cl)sc2c1
Temperature: 120 °C
Yield: 60.4 %

Procedure:
Compound 2 (1.96 g, 9.14 mmol) was dissolved in ethanol (150 mL) and purified water (100 mL), and the solution was added with anhydrous tin(II) chloride (20.7 g, 91.7 mmol). The mixture was added with 4.8 mol/L hydrochloric acid (20 mL, 96 mmol) and refluxed at 120° C. After disappearance of the starting materials was confirmed by thin layer chromatography (developing solvent: dichloromethane), the mixture was basified with aqueous sodium hydroxide. The precipitates were removed by filtration, After, ethanol was evaporated, the residue was extracted three times with ethyl acetate. Then organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/1) to obtain Compound 3 as white solid (1.02 g, 61% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O>C(#N)C>[C:14]([O:13][C:12](=[O:18])[NH:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])=[CH:3][CH:4]=1)([CH3:15])([CH3:17])[CH3:16]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (150 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (6 mL) were added benzoyl chloride (84 μL) and triethylamine (101 μL). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (212 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]([OH:31])([CH3:30])[CH3:29])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SCC)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:27]=[C:26]([C:28]([OH:31])([CH3:29])[CH3:30])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CN1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3Cl)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4Cl)c3)S2)CC1

Procedure:
5-({1-[2-Chloro-4-(1-hydroxy-1-methylethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)benzyl]-1H-indazol-5-ylmethylene}-2-ethylsulfanyl-thiazol-4-one and 1-Methyl-piperazine following General Procedure C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[S:39]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:41]1[CH:42]=[CH:43][S:39][CH:40]=1)(=[O:21])=[O:20])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccsc3)c2c1
Yield: 16.9 %

Procedure:
2-Methylsulfonyl-N-(3-thiophen-3-yl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 47 from 1 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 376 mg of 3-thiopheneboronic acid, 40 ml of dimethylformamide, 3.2 ml of a saturated aqueous sodium hydrogencarbonate solution and 42.7 mg of tetrakis(triphenylphosphine)palladium[0]. 108 mg of 2-methylsulfonyl-N-(3-thiophen-3-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid melting at 249° C. (analysis C18H15N3O4S3 % calculated C, 49.87; H, 3.49; N, 9.69; O, 14.76; S, 22.19. % found C, 49.76; H, 3.53; N, 10.03; S, 21.78).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([CH:20](OC)[O:21]C)[N:5]=1.Cl.C(Cl)(Cl)Cl.CO.C([O-])(O)=O.[Na+]>C1COCC1.O>[CH2:13]([O:12][C:10]([C:9]1[C:4]([CH:3]=[O:2])=[N:5][C:6]([CH:20]=[O:21])=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)c1cc(C(=O)OCC)c(C(OC)OC)nc1C(OC)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1cc(C(=O)OCC)c(C=O)nc1C=O
Temperature: 50 °C
Yield: 53.6 %

Procedure:
To a solution of diethyl 2,6-bis[(dimethoxy)methyl]-3,5-pyridine dicarboxylate (4.40 g, 11.9 mmol) in THF (80 ml) was added 2N HCl (80 ml), and the resulting mixture was heated to 50° C. for 30 minutes. At this time the reaction mixture was treated again with THF (80 ml) and 2N HCl (80 ml). After a total of 1.5 hours, TLC indicated that the reaction was complete (10/1 CHCl3/MeOH). The mixture was cooled and diluted with water (1 L). The pH was 0.94 and was therefore adjusted to 4.5 with solid NaHCO3. The mixture was extracted with EtOAc (2×300 ml) and the combined extracts were dried (MgSO4), filtered and concentrated to afford 1.78 g of crude 3,5-bis(ethoxycarbonyl)-2,6-pyridine dicarboxaldehyde as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 10.42 (s, 2 H), 8.49 (s, 1 H), 4.57 (q, J=7.2 Hz, 4 H), 1.51 (t, J=7.2 Hz, 6 H). 13C NMR (75 MHz, CDCl3) dc 189.83 (s), 164.67 (s), 152.17, 138.75, 130.64, 63.11 (t), 13.90 (q). MS (LR-CI) m/z 280 [M+H]+.
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH:7]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C>O>[CH3:12][N:9]1[CH2:10][CH2:11][CH:6]2[CH2:5][C:4](=[O:20])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH:7]2[CH2:8]1
Reactant: CCOC(=O)CC1CCN(C)CC1Cc1ccccc1
Solvent: O
Product: CN1CCC2CC(=O)c3ccccc3CC2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27 g of 3-benzyl-1-methyl-4-piperidine-acetic acid ethyl ester are slowly added to 250 g of polyphosphoric acid previously heated to 100°, the temperature is raised to 130° and the reaction mixture is stirred at this temperature for 2 hours. After cooling to room temperature the reaction mixture is poured on 1 liter of water, the resulting solution is washed out with ether and made alkaline with potassium carbonate (pH 9 to 10). The 1,2,3,4,4a5,11,11a-octahydro-2-methyl-6H-benzo[5,6]-cyclohepta[1,2-c]pyridin-6-one which separates as an oil, is extracted with ether, the extracts are washed with water, dried over sodium sulphate, concentrated by evaporation and distilled in a high vacuum. The mixture of isomers has a B.P. of 135°-140° 10.05 mm Hg.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([OH:17])=O)([O-:7])=[O:6]>C1C=CC=CC=1>[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([Cl:3])=[O:17])([O-:7])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: c1ccccc1
Product: O=C(Cl)Cc1ccccc1[N+](=O)[O-]

Procedure:
Thionylchloride (12.0 g) and 18.11 g of 2-nitrophenylacetic acid are weighed into a flask and allowed to stand at room temperature (~21°) for 16 hours. A stirring bar is added and the reaction driven to completion by warming at 35° for five additional hours until no solid is visible. To the red solution is added 5 ml benzene and the volatile material is removed with vacuum to give 2-nitrophenyacetyl chloride.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:19](=[O:20])[CH2:18][C:17]([CH3:16])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1CC(=O)O1
Reactant: OCC1CCCN(Cc2ccccc2)C1
Product: CC(=O)CC(=O)OCC1CCCN(Cc2ccccc2)C1
Yield: 82.7 %

Procedure:
In this reference example, 15.01 g of 1-benzyl-3-piperidine methanol and 6.76 g of diketene were reacted similarly as in Reference Example 1, and the reaction product was purified by silica gel column chromatography (eluent:n-hexane:ethyl acetate=1:1 v/v), to obtain 17.50 g of acetoacetic acid-(N-benzyl-3-piperidinylmethyl) ester (yield: 82.5%).
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][N:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[N:10]=[C:6]2[C:5]([O:19][CH3:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([CH2:28][OH:29])[CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[N:9]1[CH:8]=[C:7]2[C:2]([NH:21][C:22]3[N:27]=[CH:26][N:25]=[C:24]([CH2:28][OH:29])[CH:23]=3)=[N:3][CH:4]=[C:5]([O:19][CH3:20])[C:6]2=[N:10]1
Reactant: Nc1cc(CO)ncn1
Reactant: COc1cnc(Br)c2cn(-c3c(Cl)cccc3Cl)nc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cnc(Nc2cc(CO)ncn2)c2cn(-c3c(Cl)cccc3Cl)nc12
Yield: 41.3 %

Procedure:
A suspension of 4-bromo-2-(2,6-dichlorophenyl)-7-methoxy-2H-pyrazolo[4,3-c]pyridine (135 mg, 0.36 mmol), (6-aminopyrimidin-4-yl)methanol (50 mg, 0.4 mmol), Pd2(dba)3 (8 mg, 0.009 mmol), Xantphos (43 mg, 0.036 mmol) and cesium carbonate (235 mg, 0.72 mmol) in dioxane (3 mL) was sealed in a microwave vial, purged with nitrogen and irradiated at 150° C. for 1 hour in the microwave. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-2% methanol in ethyl acetate) to afford the title compound as a yellow solid (62 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.42 (s, 1H), 9.11 (s, 1H), 8.64 (d, J=0.9 Hz, 1H), 8.58 (d, J=1.2 Hz, 1H), 7.83 (d, J=1.3 Hz, 1H), 7.80 (s, 1H), 7.72 (dd, J=7.5, 9.2 Hz, 1H), 7.58 (s, 1H), 5.54 (t, J=6.0 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H), 3.97 (s, 3H). LCMS (Method B): RT=2.75 min, m/z: 417 [M+H+].
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C:1]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[O:13])[CH2:27][CH2:28]2)=[CH:17][CH:16]=1
Reactant: Fc1ccc(CCN2CCNCC2)cc1
Reactant: O=C(O)c1ccc2ccccc2n1
Product: O=C(c1ccc2ccccc2n1)N1CCN(CCc2ccc(F)cc2)CC1

Procedure:
Analogously to Example 1, quinaldic acid is reacted with 1-[2-(4-fluoro-phenyl)ethyl]piperazine, giving {4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}-quinolin-2-ylmethanone.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:25](C)[C:26](=O)OC(C)(C)C)[S:14]2)[CH2:10]1)C1C=CC=CC=1.B(Cl)(Cl)Cl>>[CH3:26][NH:25][C:13]1[S:14][C@H:15]2[O:16][C@H:17]([C@:18]([OH:24])([CH3:23])[C:19]([F:20])([F:21])[F:22])[C@@H:9]([OH:8])[CH2:10][C@H:11]2[N:12]=1
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2C[C@H](OCc3ccccc3)[C@@H]([C@@](C)(O)C(F)(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Product: CNC1=N[C@@H]2C[C@H](O)[C@@H]([C@@](C)(O)C(F)(F)F)O[C@@H]2S1

Procedure:
The protected material, tert-butyl ((3aR,5S,6S,7aR)-6-(benzyloxy)-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.160 g, 0.326 mmol), was deprotected using BCl3, as described for Example 20. After purification on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:12), (3aR,5S,6S,7aR)-2-(methylamino)-5-((R)-1,1,1-trifluoro-2-hydroxypropan-2-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol was obtained as a white solid (0.072 g, 73%). 1H NMR (400 MHz, CD3OD) δ 6.18 (d, J=6.8 Hz, 1H), 4.44-4.41 (m, 1H), 4.19-4.15 (m, 1H), 3.67 (d, J=7.4 Hz, 1H), 2.85 (s, 3H), 2.29-2.24 (m, 1H), 2.09-2.03 (m, 1H), 1.31 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 164.14, 127.51 (q, J=284.3 Hz), 91.42, 75.71 (q, J=27.0 Hz), 75.53, 70.18, 66.58, 33.47, 30.89, 16.96 (q, J=1.5 Hz); MS, (ES, m/z) [M+H]+ 301.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CC(C)=CCCC1CCC(CCC2C=CC(OCC3CCC(CCCCC)=CC3)=CC=2)CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:19][CH:20]=2)=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCBr
Reactant: Oc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1
Agent: CCCCCC1=CCC(COc2ccc(CCC3CC=C(CCC=C(C)C)CC3)cc2)CC1
Product: CCCCCCCCCCOc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1

Procedure:
The reaction between 5-benzyloxy-2-(4-hydroxyphenyl)pyrimidine (prepared essentially according to the procedure of E. P. Janulis et al., U.S. Pat. No. 5,399,291) and bromodecane is essentially that used for synthesis of ether 2H.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(O)C>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[C:8]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)=[O:9])[CH2:27][CH2:26]1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(CC(O)COc2ccccc2C(=O)Nc2cccc3[nH]ccc23)CC1

Procedure:
1.8 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)-benzamide in 36 ml of ethanol and 6.5 ml of N-methyl piperazine was refluxed for 1 hour and the solvents were eliminated under reduced pressure. The residue was chromatographed over silica (eluent:chloroform-ethanol, 9-1) to obtain 1.77 g of 2-[3-(4-methyl-1-piperazinyl)-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamid
Reaction SMILES: [CH3:1][O:2][C:3](=[O:54])[CH2:4][CH2:5][N:6]([C:15](=[O:53])[C@@H:16]([NH:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[CH2:17][C:18]1[N:19]=[CH:20][N:21](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:22]=1)[CH2:7][C:8]([O:10]C(C)(C)C)=[O:9].FC(F)(F)C(O)=O>>[CH3:1][O:2][C:3](=[O:54])[CH2:4][CH2:5][N:6]([C:15](=[O:53])[C@@H:16]([NH:42][C:43]([O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:44])[CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)[CH2:7][C:8]([OH:10])=[O:9]
Reactant: COC(=O)CCN(CC(=O)OC(C)(C)C)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCN(CC(=O)O)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Yield: 91 %

Procedure:
The compound from Step 2 (1.38 g, 1.9 mmol) was treated with 95% aqueous trifluoroacetic acid for 1.5 hours. The solvent was reduced to a few milliliters, and pipetted into 200 mL of ether/hexanes. The product was allowed to precipitate overnight at −40° C. The solid was collected, rinsed and dried; 0.75 g (91% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](Cl)=[O:34]>C1COCC1>[O:24]=[C:23]1[NH:22][N:21]=[C:20]([CH2:25][CH2:26][CH3:27])/[C:19]/1=[C:11]1/[NH:12][C:13]2[C:18]([C:9]([S:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:33]([C:29]4[S:28][CH:32]=[CH:31][CH:30]=4)=[O:34])=[CH:7][CH:6]=3)=[CH:10]/1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(Cl)c1cccs1
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)c3cccs3)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 2-thiophene carbonyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H) 1.28-1.37 (m, 2H) 2.26 (t, J=7.20 Hz, 2H) 6.80 (s, 1H) 7.27 (t, J=4.29 Hz, 1H) 7.63 (t, J=7.58 Hz, 1H) 7.75 (d, J=8.34 Hz, 2H) 7.86 (t, J=7.58 Hz, 1H) 7.92 (d, J=5.05 Hz, 2H) 8.05 (d, J=8.59 Hz, 2H) 8.08 (d, J=3.79 Hz, 1H) 8.15 (d, J=8.08 Hz, 1H) 10.56 (s, 1H); ESI-MS: m/z calc'd for C26H22N4O2S2 486.61. found 487.2 (M+H)+.