Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([OH:21])([CH3:20])[CH3:19])[CH2:4][CH2:3]1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH:27]([CH:32]=O)[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH:27]([CH2:32][NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=4[N:10]=[C:9]3[C:18]([OH:21])([CH3:19])[CH3:20])[CH2:6][CH2:7]1)[CH2:26]2
Reactant: O=CC1Cc2ccc(F)cc2C1
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCC(N)CC1
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2[C@H]1CC[C@@H](NCC2Cc3ccc(F)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of 2-[1-(4-amino-cyclohexyl)-5-methyl-1H-benzoimidazol-2-yl]-propan-2-ol (prepared as cis/trans-isomer mixture) and 5-fluoro-indan-2-carbaldehyde. The less polar of the two substances isolated by chromatography gave cis-2-(1-{4-[(5-fluoro-indan-2-ylmethyl)-amino]-cyclohexyl}-5-methyl-1H-benzoimidazol-2-yl)-propan-2-ol. The analysis of the 1H-NMR confirmed the cis-conformation of the cyclohexane. LC-MS showed a single peak, C27H34FN3O (m/e) calcd 435.2686, obsd 436.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-])=O.[C:22]([C:24]1[O:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1)#[N:23].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd]>[N:16]1([C:6]2[CH:7]=[CH:8][C:9]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[C:4]([NH:1][C:29]([C:27]3[O:28][C:24]([C:22]#[N:23])=[CH:25][CH:26]=3)=[O:30])[CH:5]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: N#Cc1ccc(C(=O)O)o1
Reactant: O=[N+]([O-])c1cc(N2CCOCC2)ccc1N1CCCCC1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C(=O)Nc2cc(N3CCOCC3)ccc2N2CCCCC2)o1
Yield: 45.4 %

Procedure:
The title compound was prepared following the procedure of Example 5, step (b) using 76.7 mg (0.318 mmol) of 4-(3-nitro-4-piperidin-1-yl-phenyl)-morpholine (as prepared in the previous step), 50 mg of 10% palladium on carbon (50% by weight water), 43.6 mg (0.318 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 55.5 μL (0.636 mmol) of oxalyl chloride, and 83.1 μL (0.477 mmol) of DIEA. The resulting residue was chromatographed on a 10-g silica SPE column with 15-25% EtOAc-hexane to afford 54.9 mg (45%) of the title compound as a light yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.97 (br s, 1H), 8.17 (d, 1H, J=2.8 Hz), 7.23, 7.26 (AB q, 2H, J=3.7 Hz), 7.13 (d, 1H, J=8.7 Hz), 6.66 (dd, 1H, J=8.7, 2.8 Hz), 3.84-3.87 (m, 4H), 23.17-3.19 (m, 4H), 2.75-2.85 (m, 4H), 1.77-1.82 (m, 4H), and 1.5-1.7 (br m, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H24N4O3, 381.2 (M+H), found 381.2.
Reaction SMILES: [CH3:1][S-:2].[Na+].[PH:4](=[O:7])([OH:6])[OH:5].[CH2:8]([C:10]([CH2:38][CH3:39])([CH:12](I)[C:13]1[N:17]=[CH:16][N:15]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1)[CH3:11])[CH3:9].O>C(O)C>[PH:4](=[O:5])([OH:7])[OH:6].[CH2:8]([C:10]([CH2:38][CH3:39])([CH:12]([S:2][CH3:1])[C:13]1[N:17]=[CH:16][N:15]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1)[CH3:11])[CH3:9]
Reactant: CCC(C)(CC)C(I)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C[S-]
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(C)(CC)C(SC)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 5 h
Yield: 68.9 %

Procedure:
Sodium thiomethoxide (0.24 g) was added to a stirred solution of diethyl 3-iodo-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (1.0 g, prepared as described in Example 30) in ethanol (10 ml). The mixture was stirred for five hours, allowed to stand overnight, poured into water and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-methylthio-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.60 g, m.p. 97-98° C.). NMR (CDCl3): δ 1.3(6H,dt), 1.7-1.9(2H,m), 1.9(3H,s), 2.2-2.4(2H,m), 3.9(1H,t), 4.05(4H,m), 7.1(6H,m), 7.3(9H,m), 7.9(1H,s). FAB M/S: MH+ 536.
Reaction SMILES: [C:1](=[O:43])([O:33][C:34]1C=CC([N+]([O-])=O)=C[CH:35]=1)[O:2][CH2:3][O:4][C:5]1[C:6](=[O:32])[C:7]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])=[O:21])=[CH:8][N:9]2[C:14]=1[C:13](=[O:15])[N:12]1[C@@H:16]([CH3:19])[CH2:17][O:18][C@@H:11]1[CH2:10]2.OCC[N:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52].C(N(CC)CC)C>CN(C1C=CN=CC=1)C>[C:1](=[O:43])([O:33][CH2:34][CH2:35][N:47]1[CH2:51][CH2:50][CH2:49][C:48]1=[O:52])[O:2][CH2:3][O:4][C:5]1[C:6](=[O:32])[C:7]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])=[O:21])=[CH:8][N:9]2[C:14]=1[C:13](=[O:15])[N:12]1[C@@H:16]([CH3:19])[CH2:17][O:18][C@@H:11]1[CH2:10]2
Reactant: O=C1CCCN1CCO
Reactant: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)Oc4ccc([N+](=O)[O-])cc4)c3C(=O)N12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCCN4CCCC4=O)c3C(=O)N12

Procedure:
The title compound was prepared from {[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl 4-nitrophenyl carbonate (50 mg, 0.83 mmol), 1-(2-hydroxyethyl)-2-pyrrolidinone (9 μL, 0.083 mmol), triethylamine (35 μL, 0.250 mmol), and DMAP (10 mg, 0.083 mmol), in a process similar to that described in example 10. Purification by silica-gel chromatography and reverse-phase hplc afforded the title compound as a white solid. 1H NMR (CDCl3) δ 10.28 (m, 1H), 8.45 (s, 1 H), 7.32 (m, 1H), 6.80 (m, 2H), 5.93 (d, J=6.8 Hz, 1H), 5.80 (d, J=6.4 Hz, 1H), 5.28 (dd, J=10, 3.6 Hz, 1H), 4.64-4.23 (m, 8H), 3.94 (m, 1H), 3.68-3.50 (m, 4H), 2.42 (t, J=8 Hz, 2H), 2.02 (m, 2H), 1.37 (d, J=6 Hz, 3H). ES+ MS: 591 (M+1).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21](Br)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].[CH3:34][C:35]1[N:36]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:37]=[C:38]([Sn](CCCC)(CCCC)CCCC)[N:39]=1.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.ClCCl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:38]4[N:39]=[C:35]([CH3:34])[N:36]([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)[CH:37]=4)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2ccccc2)c(C)n1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(Br)cnc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Cc1nc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)cn3COCC[Si](C)(C)C)cn1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (115 mg, 0.188 mmol) and 2-methyl-1-phenyl-4-tributylstannanyl-1H-imidazole (101 mg, 0.225 mmol) were dissolved in 1.9 mL of DMF and the mixture was purged with Ar gas. Tetrakis(triphenylphosphine)palladium (10.8 mg, 0.0094 mmol) and then copper (I) iodide (7.1 mg, 0.038 mmol) were added and the reaction was sealed and stirred in an 80° C. oil bath for 18 h. The reaction was cooled and water, dichloromethane, and sodium bicarbonate solution were added. The layers were separated, and the aqueous layer was extracted twice more with dichloromethane. The combined organic layers were washed with water and then brine, and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to provide 68 mg (59%) of 2-(2-methyl-1-phenyl-1H-imidazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide. (M+H)+=611.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[N:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1ccc(C2=CCCCC2)nc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(C2CCCCC2)nc1
Reaction time: 3 h

Procedure:
To a solution of 6-cyclohex-1-enyl-pyridin-3-ol (2.2 g, 12.6 mmol) in methanol (45 ml) was added 10% Pd/C (0.22 g) under N2. This mixture was stirred under hydrogen (1 atm) for 3 h. The reaction mixture was filtered through celite. The filtrate was concentrated to a solid (2.2 g) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:16]O.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:10]1([CH2:9][O:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:16][Br:19])=[C:2]([CH3:1])[CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(OCc2ccccc2)ccc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
To a solution of {2-methyl-4-[(phenylmethyl)oxy]phenyl}methanol (1.49 g, 6.53 mmol) in DCM (20 ml) under nitrogen in an ice-water bath was added a solution of phosphorus tribromide (0.62 ml, 6.57 mmol, Aldrich) in DCM (10 ml). The solution was allowed to warm to ambient temperature and stirred for 3 h. The reaction mixture was poured onto ice-water (70 ml) and saturated aqueous sodium hydrogen carbonate (30 ml). The mixture was diluted with DCM (50 ml) and the phases separated. The aqueous extract was washed with dichloromethane DCM (20 ml). The combined organic extracts were washed with water (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to leave 4-(bromomethyl)-3-methylphenyl phenylmethyl ether as a yellow oil (1.72 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][S:6][C:7]1[C:11]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[N:10][S:9][N:8]=1)[CH3:2].S(=O)(=O)(O)[OH:20].B1([O-])OO1.O.O.O.O.[Na+]>CO>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6]([C:7]1[C:11]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[N:10][S:9][N:8]=1)=[O:20])[CH3:18]
Reactant: O=S(=O)(O)O
Reactant: CCN(CC)CCSc1nsnc1-n1ccnc1
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: O
Solvent: CO
Product: CCN(CC)CCS(=O)c1nsnc1-n1ccnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A cold (0° C.) solution of the compound of Example 10 in methanol istreated slowly with excess 30% sulfuric acid an then sodium perborate tetrahydrate (10 equivalents) is added. The mixture is stirred at 0° C. for 2 hrs and then at ambient temperature for 2 hrs. The methanol is removed in vacuo and the residue basified with 50% sodium hydroxide and filtered. The filter cake is washed with methylene chloride and the aqueous filtrate extracted with the methylene chloride washings. The combined extract is washed with water, dried, and concentrated to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][N:28]3C2CCCCO2)[C:5]([NH:8][C:9]2[C:10]3[CH:11]=[N:12][N:13](C4CCCCO4)[C:14]=3[CH:15]=[CH:16][CH:17]=2)=[N:6][CH:7]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][NH:28]3)[C:5]([NH:8][C:9]2[C:10]3[CH:11]=[N:12][NH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)=[N:6][CH:7]=1
Reactant: Cc1nc(-c2cc(Cl)cnc2Nc2cccc3c2cnn3C2CCCCO2)c2ncn(C3CCCCO3)c2n1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(-c2cc(Cl)cnc2Nc2cccc3[nH]ncc23)c2nc[nH]c2n1
Temperature: 40 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A solution of N-(5-chloro-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (96.8 mg, 178 μmol) in DCM/MeOH (4.0 mL, 1:1) was treated with (+/−)-10-camphorsulfonic acid (91 mg, 391 μmol) and the stirred mixture placed in an oil bath at 40° C. The heater was turned off and the mixture stirred for 16 h. LCMS showed predominantly monodeprotection, so an additional 90 mg of CSA was added (4.4 equiv. total). The mixture was heated at 40° C. until LCMS indicated complete deprotection. The mixture was cooled and purified by ion exchange chromatography (washing with MeOH, eluting off with 2 N NH3/MeOH). The product was concentrated, taken up in MeOH (3 mL), sonicated and allowed to stand. N-(5-Chloro-3-(2-methyl-9H-purin-6-yl)pyridin-2-yl)-1H-indazol-4-amine (55 mg, 82% yield) crystallized out and was collected by filtration as an orange solid. 1H NMR of free base thus obtained gives broad signals, so a small amount was converted to the HCl salt for better 1H NMR analysis by dissolving in MeOH containing 2 drops 2 M aqueous HCl followed by concentration to dryness. HCl salt: 1H NMR (400 MHz, d6-DMSO) δ 11.29 (br. s., 1H); 10.17 (br. s., 1H); 10.04 (s, 1H); 9.27 (d, J=2.69 Hz, 1H); 8.93 (s, 1H); 8.40 (s, 1H); 8.30 (d, J=2.69 Hz, 1H); 7.89 (d, J=9.54 Hz, 1H); 7.52 (d, J=9.54 Hz, 1H); 2.15 (s, 3H). m/z (ESI, +ve) 377.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)=[O:29]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cccc(Cl)c4)nc3cc21

Procedure:
3-Chloro-N-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3-chlorobenzoyl chloride (113 μl, 0.89 mmol). The title compound was obtained as light brown powder (105 mg, 29%).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=2[NH:6][C:5]1=[O:14].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:17][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=2[NH:6][C:5]1=[O:14]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2c(c1)[nH]c(=O)n2CCO
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCl
Reaction time: 5 h
Yield: 42 %

Procedure:
To a stirred mixture of 26 parts of 1,3-dihydro-1-(2-hydroxyethyl)-5-methyl-2H-benzimidazol-2-one and 390 parts of trichloromethane are added dropwise 48 parts of sulfinyl chloride at room temperature. Upon completion, stirring is continued for 5 hours at reflux. The reaction mixture is evaporated. The oily residue is heated with 2,2'-oxybispropane and a small amount of 2-propanol and the whole is stirred with activated charcoal. The latter is filtered off and the filtrate is stirred at room temperature till all the product is precipitated. It is filtered off and dried, yielding 12 parts (42%) of 1-(2-chloroethyl)-1,3-dihydro-5-methyl-2H-benzimidazol-2-one; mp. 120° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[CH:6]=[N:7][CH:8]=1.[H-].[Na+].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>CN(C=O)C>[CH3:33][N:32]1[C:25]2[N:26]([C:27](=[O:29])[N:28]=[C:23]([O:17][CH2:16][C:13]3[CH:12]=[CH:11][C:10]([O:9][C:5]4[CH:6]=[N:7][CH:8]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:4]=4)=[CH:15][CH:14]=3)[CH:24]=2)[CH2:30][CH2:31]1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2cncc(C(F)(F)F)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3cncc(C(F)(F)F)c3)cc1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol (250 mg, 0.929 mmol) in DMF (5 mL), sodium hydride (66.9 mg, 2.79 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (172 mg, 0.929 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=[O:14].Br[CH2:16][C:17](=[O:33])[CH2:18][C@H:19]1[C@H:24]([O:25][CH3:26])[CH2:23][CH2:22][CH2:21][N:20]1[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:12][CH3:13])[N:8]=[CH:7][N:6]([CH2:16][C:17](=[O:33])[CH2:18][C@H:19]1[C@H:24]([O:25][CH3:26])[CH2:23][CH2:22][CH2:21][N:20]1[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[C:5]2=[O:14]
Reactant: CSc1cc2nc[nH]c(=O)c2cc1Cl
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(SC)c(Cl)cc2c1=O

Procedure:
In the manner of Example 4, 0.679 g (0.003 mol) of 6-chloro-7-methylthioquinazolin-4(3H)-one and 1.0 g (0.003 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate were converted into the title compound: yield 0.56 g (39%). 1H--NMR(CDCl3) 1.4-2.2 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.6 (singlet, 3H, SCH3), 2.8-3.4 (multiplet, 4H, NCH2, COCH2CH), 3.4 (singlet, 3H, OCH3), 4.0 (broad singlet, 1H, CHNCO), 4.6 (doublet, 2H, CH2CH=CH2), 5.0 (singlet, 2H, NCH2CO), 5.0-5.5 (multiplet, 2H, CH=CH2), 5.6-6.1 (octet, 1H, CH2 =CH), 7.4 (singlet, 1H, aromatic H), 7.9 (singlet, 1H, N=CH--N), 8.2 (singlet, 1H, aromatic H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.O>[CH2:20]([O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[Br:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.5 %

Procedure:
2-Bromo-4-(trifluoromethoxy)phenol (Preparation 8; 5 g, 20 mmol) was dissolved in N,N-dimethylformamide (60 ml), and potassium carbonate (5.4 g, 40 mmol) was added, followed by benzyl bromide (3.5 ml, 30 mmol), and the reaction was stirred at ambient temperature for 15 hours. The reaction was diluted with water (150 ml) and extracted into ethyl acetate (3×60 ml). The combined organic fractions were washed with water (100 ml), brine (100 ml), dried (MgSO4) and evaporated in vacuo. Purification on silica, eluting with 2% and 5% ethyl acetate in hexane gave the title compound as a clear oil (6.7 g, 96%). 1H NMR (250 MHz, CDCl3) δ5.47 (2 H, s), 7.23 (1 H, d, J=9 Hz), 7.43 (1 H, dd J=8.2, 2.9 Hz), and 7.75 (6 H, m).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH3:19])=[CH:10][C:9]=1[CH2:20][OH:21].CI.O>C1COCC1>[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH3:19])=[C:10]([CH3:1])[C:9]=1[CH2:20][OH:21]
Reactant: [Li]CCCC
Reactant: COc1cc(CO)c(OC)c2ccccc12
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: COc1c(C)c(CO)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
n-Butyllithium (7.3 mL, 18.3 mmol, 2.5 M in hexanes) was added dropwise via syringe to a solution of 23a (1.00 g, 4.58 mmol) in THF (30 mL) at −78° C. under argon. The solution was slowly warmed to room temperature and stirred for 1 h. Methyl iodide (0.34 mL, 5.50 mmol) was added dropwise and the solution was stirred for 20 min. Water (8 mL) was added and the mixture was extracted with EtOAc (4×). The combined organic layers were dried (MgSO4), filtered and evaporated. Column chromatography of the crude product (45:55 EtOAc:hexanes) afforded 23b (0.61 g, 57%) as a yellow solid; Rf=0.59 (45:55 EtOAc:hexanes); mp=116-117° C.; lit mp=118-121° C.25; 1H NMR (CDCl3): δ 8.07 (dd, 2H), 7.51 (m, 2H), 4.94 (s, 2H), 3.98 (s, 3H), 3.88 (s, 3H), 2.52 (s, 3H), 1.73 (bs, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[C:20]([O:32]CC3C=CC=CC=3)[CH:19]=2)[OH:17])[O:12][C:11](=[O:40])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Ni]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:32])[CH:19]=2)[OH:17])[O:12][C:11](=[O:40])[CH:10]=1
Reactant: [H][H]
Reactant: O=c1cc(OCc2ccccc2)cc(CC(O)c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)o1
Agent: [Ni]
Solvent: CCO
Product: O=c1cc(O)cc(CC(O)c2ccc(O)c(O)c2)o1
Yield: 70 %

Procedure:
35.6 g (66.6 mmol) 4-benzyloxy-6-[2-[3,4-dibenzyloxyphenyl)-2-hydroxy-ethyl)]-2H-pyran-2-one (VI) was hydrogenated for 6 hours at room temperature under a hydrogen pressure of 44 mbar in 1200 ml ethanol using 10 g W2 Raney nickel. After taking up 4.4 l hydrogen the catalyst was removed by suction filtration and it was rewashed several times with tetrahydrofuran. The evaporated filtrates yielded 12.2 g (70%) VII after triturating with ether, melting point 153° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][NH2:25])=[O:23])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:26](O)(=O)C.C(=N)N.CS(C)=O.O(C(C)C)C(C)C>CC(C)CC(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:26]=[N:25][NH:24][C:22]4=[O:23])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)NN)cc3)CC2)cc1
Reactant: CC(=O)O
Agent: N=CN
Solvent: CS(C)=O
Solvent: CC(C)OC(C)C
Solvent: CC(=O)CC(C)C
Product: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Temperature: 100 °C
Yield: 28 %

Procedure:
A mixture of 3.4 parts of N-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}hydrazinecarboxamide, 3 parts of methanimidamide acetate and 10 parts of dimethyl sulfoxide is stirred and heated for 2 hours at 100° C. The reaction mixture is cooled and poured onto a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The precipitated product is filtered off and crystallized from N,N-dimethylformamide (activated charcoal), yielding 1 part (28%) of 2,4-dihydro-4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-3H-1,2,4-triazol-3-one; mp.+300° C.