Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.O=P(Cl)(Cl)[Cl:20]>CN(C=O)C>[Cl:20][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1
Reactant: COc1cccc2c(O)cc(C(F)(F)F)nc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cccc2c(Cl)cc(C(F)(F)F)nc12
Reaction time: 8 h

Procedure:
4-Hydroxy-8-methoxy-2-trifluoromethylquinoline (18.77 g) is dissolved in. 450 mL 8:1 C2Cl2:DMF. POCl3 (50 mL) is added dropwise and the reaction is allowed to stir overnight. The reaction is then poured into 500 mL ice/H2O and the aqueous is extracted 2× with CH2Cl2. The organic portions are combined, washed 1× with brine, dried over MgSO4, and evaporated. The resulting oil crystallizes upon standing. The solid is recrystallized from 95% EtOH. A second crop of crystals could be obtained by concentrating down the EtOH filtrate. The total yield of product is 15.36 g.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[NH:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][C:25]=4[C:16]=3[C:15]3[C:28](=[O:32])[O:29][C:30](=O)[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([O:33][CH3:34])[CH:11]=2.[NH3:36]>C(O)C>[CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[NH:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][C:25]=4[C:16]=3[C:15]3[C:28](=[O:32])[NH:36][C:30](=[O:29])[C:14]=3[C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([O:33][CH3:34])[CH:11]=2
Reactant: COc1ccc2[nH]c3c(c4c(c5c6cc(OC)ccc6n(CCCN(C)C)c35)C(=O)OC4=O)c2c1
Reactant: N
Solvent: CCO
Product: COc1ccc2[nH]c3c(c4c(c5c6cc(OC)ccc6n(CCCN(C)C)c35)C(=O)NC4=O)c2c1

Procedure:
510 mg (1.08 mmol) 12-(3-Dimethylaminopropyl)-6,7,12,13-tetrahydro-3,9-dimethoxy-5,7-dioxoindolo-[2,3-a]furano[3.4-c]carbazole are heated in an autoclave for 24 hours at 140° C. in 40 ml of a saturated solution of ammonia in ethanol. After cooling, the precipitate obtained is filtered off with suction, chromatographed on silica gel with toluene/ethanol (10:1 v/v) and the fraction with the Rf 0.25 in toluene/ethanol (5:1 v/v) is isolated. 12-(3-Dimethylaminopropyl)-6,7,12, 13-tetrahydro-3,9-dimethoxy-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole is obtained in the form of yellow crystals which decompose from about 230° C. This compound can also be prepared from the same starting material by reaction with hexamethyldisilazane and methanol in dimethylformamide analogously to the process described in the literature (Tetrahedron Lett., 1990, 31, 5201).
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1.Br[CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24]>>[CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[CH:16][CH:15]=1)[C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CN(c1ccc(O)cc1)c1nnc2cc(Cl)ccc2n1
Reactant: COC(=O)C(C)Br
Product: COC(=O)C(C)Oc1ccc(N(C)c2nnc3cc(Cl)ccc3n2)cc1

Procedure:
4-[N-Methyl-N-(7-chloro-1,2,4-benzotriazin-3-yl)-amino]phenol was reacted with methyl 2-bromopropionate following essentially the same procedure as that described in Example 1 part (b) to give the title compound, mp 120° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=12.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:19]([NH:26][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH3:18])[C:6]=12)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(Br)c12
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(-c2cnn(C)c2)cn2ncc(NCc3ccccc3)c12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
3-bromo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (25.0 mg, 0.081 mmol), benzyl amine (12.0 mg, 0.011 mmol), tris[dibenzylideneacetone]dipalladium (0) (1.9 mg, 0.0020 mmol), and tert-butyl X-phos (3.5 mg, 8.1 mmol) were suspended in toluene (1.6 ml), sparged with argon for 3 minutes, then heated to 100° C. After 12 hours, the reaction mixture was concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give N-benzyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-amine 1H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 1H); 8.17 (s, 1H); 7.91 (s, 1H); 7.38 (d, 2H); 7.29 (t, 2H); 7.25 (s, 1H); 7.20 (t, 1H); 6.44 (s, 1H); 4.92 (t, 1H); 4.23 (d, 2H); 3.93 (s, 3H); 3.83 (s, 3H). LRMS (ESI) calculated for C19H20N5O [M+H]+, 334.2; found 334.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:10]1[CH:11]=[C:12]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:25])([F:24])[F:23])[NH:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:36])[CH:5]([C:10]1[CH:11]=[C:12]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([F:23])([F:24])[F:25])[N:17]2[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2)c1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCC(C(F)(F)F)N2Cc2ccccc2)c1
Temperature: 150 °C

Procedure:
4-Methyl-2-[4′-trifluoromethyl-5-(6-trifluoromethyl-piperidin-2-yl)-biphenyl-3-yl]-pentanoic acid ethyl ester, compound 7b (32 mg, 0.062 mmol), Benzyl bromide (55 μl, 0.46 mmol), DIEA (110 μl, 0.62), and tetrabutylammonium iodide (TBAI)(10 mg) in acetonitrile (0.5 mL) were combined and heated under microwave conditions 150° C. for 30 minutes. The reaction was diluted with EtOAc, washed with brine, sat. NaHCO3, and brine, dried over magnesium sulfate and filtered. Purification by silica gel chromatography gave the product as yellow oil. (56 mg, quant.) (M+H) 605.65, Found 606.2
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)=[CH:4][CH:3]=1.[O-]CC.[Na+].Cl[CH2:20][C:21](=O)[CH3:22]>C(O)C>[CH3:1][C:2]1[S:6][C:5]([CH:7]2[CH2:8][C:9](=[O:14])[C:10]3[C:21]([CH3:22])=[CH:20][O:13][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: Cc1ccc(C2CC(=O)CC(=O)C2)s1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C2CC(=O)c3c(C)coc3C2)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(5-methyl-2-thienyl)cyclohexane-1,3-dione (mp178-179° C.; 1.04 g) in ethanol (15 ml) was added sodium ethoxide (0.37 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.45 ml), and the mixture was stirred at 100° C. for 1 hour. The reaction solution was cooled concentrated under reduced pressure. To the residue was added mesitylene(15 ml), and the mixture was stirred at 150° C. for 4 hours. The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(5-methyl-2-thienyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]([O:24]C)=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:3]([C:22]([OH:24])=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc2c(cc1C)[nH]c(=O)c1cnn(C3CCOCC3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)O
Temperature: 60 °C
Reaction time: 20 h
Yield: 98.7 %

Procedure:
To a mixture of 2.63 g of methyl 7-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-8-carboxylate and 52 mL of methanol was added 10.2 mL of a 3 M aqueous sodium hydroxide solution, followed by stirring at 60° C. for 20 hours. The insoluble material was filtered, and the filtrate was adjusted to pH 2 with concentrated hydrochloric acid, and stirred for 1 hour. The precipitated powder was collected by filtration and dried under reduced pressure to obtain 2.49 g of 7-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid as powder.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([OH:24])=[O:23])[CH2:3]1.[N+](=[CH2:27])=[N-]>CO.CCOCC>[OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([O:24][CH3:27])=[O:23])[CH2:3]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 0.17 h

Procedure:
A solution of 3α-hydroxy-11-oxo-5α-androstane-17β-carboxylic acid (350 mg.) in methanol (20 ml.) and ether (10 ml.) was treated with a dry ethereal solution of diazomethane. After 10 minutes, any unreacted diazomethane was destroyed by the addition of a drop of glacial acetic acid and the mixture was evaporated to small bulk. This was taken up in ether and washed with dilute sodium hydrogen carbonate solution, with water, dried and evaporated to a foam. The product was crystallised from acetone and petrol to give title compound (28/ mg.) as off white needles; m.p. 162 163°; [α]D + 77°.
Reaction SMILES: [CH2:1]([C@H:4]1[C:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.ClCCl>O1CCOCC1>[CH2:1]([C@H:4]1[C:21]2[C@:16]([CH3:23])([CH:17]=[CH:18][C:19](=[O:22])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3]
Reactant: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12
Reaction time: 6 h
Yield: 58.9 %

Procedure:
To a solution of 6β-propargyl-4-androstene-3,17-dione (1) (160 mg, 0.5 mmol) in dry dioxane (30 mL) was added dichlorodicyanobenzoquinone (DDQ, 150 mg, 0.6 mmol), and the reaction mixture was refluxed with stirring for 6 hours. Dilution with 30 mL dichloromethane followed by washing (1% NaOH, water), drying and evaporation in vacuo, gave 125 mg of crude product. The residue was purified by chromatography over silica gel and the product was recrystallized from acetone/hexane to give 95 mg (60% yield) of the title compound (12).
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][S:4][CH:3]=1.[C:8](Cl)(=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1.CCCCCC>[C:8]([NH:1][C:2]1[C:6]([NH:7][C:8](=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][S:4][CH:3]=1)(=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1cscc1N
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCC(=O)Nc1cscc1NC(=O)CCCCCCCCCCCCCCC
Yield: 70 %

Procedure:
This compound was prepared in a yield of 70% of theory starting from 3,4-diaminothiophene and palmitoyl chloride (boiling point 141° C. at 1.4 mbar) in a similar manner to above. The melting point was 107-109° C. (from toluene-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(OCC)(=O)C>[C:24](=[O:25])([O:26][CH2:27][CH3:28])[O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[Cl:9]
Reactant: CCOC(=O)Cl
Reactant: Oc1c(Cl)cc(-c2ccccc2)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1c(Cl)cc(-c2ccccc2)cc1Cl
Reaction time: 8 h
Yield: 90.7 %

Procedure:
40.6 g (0.17 mol) of 3,5-dichloro-4-hydroxybiphenyl (prepared according to J. C. Colbert et al., JACS 56, 202 (1934)) and 17.2 g (0.17 mol) of triethylamine are dissolved in 170 ml of ethyl acetate and admixed dropwise with 18.4 g (0.17 mol) of ethyl chloroformate at 10° C. The reaction solution is stirred overnight and washed with water, and the organic phase is concentrated. For further purification, the crude product (51.2 g) is chromatographed over silica gel using the system chloroform. 48 g (yield 90.8% of theory) of (2,6-dichloro-4-phenyl-phenyl) ethyl carbonate are obtained as an oil, log p (pH 7.5): 4.65.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH2:36]([O:38][CH:39]1[O:43][C@H:42]([CH2:44]O)[C@@H:41]([CH2:46][OH:47])[O:40]1)[CH3:37]>>[C:12]([C:9]1[CH:8]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([O:31][CH2:44][C@@H:42]3[C@@H:41]([CH2:46][OH:47])[O:40][CH:39]([O:38][CH2:36][CH3:37])[O:43]3)=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCOC1O[C@H](CO)[C@@H](CO)O1
Product: CCOC1O[C@H](CO)[C@@H](COc2c(C(C)(C)C)cc(SC(C)(C)Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc2C(C)(C)C)O1

Procedure:
The title compound was prepared using the same procedure as described in Ex-1A starting from probucol and 2-ethoxy-1,3-dioxolane-4(R),5(R)-dimethanol as a white solid (10.3 g, 35%), mp 60–62° C. 1H-NMR (300 MHz, CDCl3) δ 7.56 (s, 2H), 7.44 (s, 2H), 5.89 (s, 1H), 5.36 (s, 1H), 4.75–4.78 (m, 1H), 4.19–4.24 (m, 2H), 3.92–3.99 (m, 2H), 3.84 (dd, 1H, J=10.0, 4.2 Hz), 3.60–3.74 (m, 2H), 2.79 (dd, 1H, J=9.1, 3.3 Hz). 1.43–1.45 (m, 42H), 1.28 (t, 3H, J=7.2 Hz). HRMS (ESI) calcd for C38H60O6S2 (M+Na), 699.3729; found, 699.3756. Anal. calcd. for C38H60O6S2: C, 67.42, H, 8.93, S, 9.47; found: C, 67.04, H, 9.00, S, 8.86.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29]([OH:31])=O.[CH2:50]([NH2:58])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][C:45]([F:46])([F:47])[F:48])=[CH:40][CH:39]=3)[C:33]2=[O:49])[S:27][C:28]=1[C:29]([NH:58][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:31]
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: NCCc1ccccc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCCc1ccccc1
Yield: 7 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with phenethylamine, the title compound was obtained as a white powder in 7% yield: mp 184-185° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32-7.17 (m, 9H), 5.62 (br s, 1H), 4.47 (s, 2H), 4.09-4.03 (m, 2H), 3.67-3.60 (m, 2H), 3.47-3.42 (m, 2H), 2.88 (d, J=6.9 Hz, 2H), 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.5, 157.2, 155.4, 152.3, 148.9, 138.7, 134.4, 129.7, 128.8, 128.7, 126.6, 122.1, 121.4, 118.0, 47.3, 42.0, 41.8, 41.1, 35.7, 17.1; MS (ES+) m/z 505.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.C([S:22][C@H:23]1[CH2:28][CH2:27][C@H:26](/[CH:29]=[CH:30]/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[CH2:25][CH2:24]1)(=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([S:22][C@H:23]1[CH2:28][CH2:27][C@H:26](/[CH:29]=[CH:30]/[CH:31]=[CH:32]/[C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:38]=2)[CH2:25][CH2:24]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CC(=O)S[C@H]1CC[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](S[C@H]1CC[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
Reaction was carried out in the same manner as in Example 1 using (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane and trans-1-(acetylthio)-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadien-1-yl]cyclohexane as described in Reference example 43 to obtain the title compound having a melting point of 74 to 76° C. in a yield of 59%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:23][CH2:24][C@@H:25]([C@H:27]2[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28]2)[OH:26])[C:5]2[N:6]([C:8]([C:11]3[CH:22]=[CH:21][C:14]([C:15]([NH:17][CH:18]4[CH2:20][CH2:19]4)=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.B(O)O.C(=O)(O)[O-].[Na+].[CH2:42](O)[CH3:43]>C1(C)C=CC=CC=1>[CH:18]1([NH:17][C:15](=[O:16])[C:14]2[CH:21]=[CH:22][C:11]([C:8]3[N:6]4[N:7]=[C:2]([C:5]5[N:6]([CH3:8])[N:7]=[CH:43][CH:42]=5)[CH:3]=[C:4]([NH:23][CH2:24][C@@H:25]([C@H:27]5[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28]5)[OH:26])[C:5]4=[N:10][CH:9]=3)=[CH:12][CH:13]=2)[CH2:20][CH2:19]1
Reactant: CC1(C)OC[C@H]([C@@H](O)CNc2cc(Cl)nn3c(-c4ccc(C(=O)NC5CC5)cc4)cnc23)O1
Reactant: CCO
Agent: O=C([O-])O
Agent: OBO
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1nccc1-c1cc(NC[C@H](O)[C@H]2COC(C)(C)O2)c2ncc(-c3ccc(C(=O)NC4CC4)cc3)n2n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a mixture of 52 mg (94 mot) 4-[6-chloro-8-({(2S)-2-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl}amino)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropylbenzamide which was prepared according to intermediate example 192a, 33 mg 1-methyl-1H-pyrazol-5-yl) boronic acid, 6.5 mg tetrakis(triphenylphosphin)palladium in 1 mL of ethanol and 1 mL of toluene was added 0.26 mL of an aqueous 10% sodiumbicarbonate solution and the mixture was stirred at 120° C. for 2 hours under microwave irradiation. Then the mixture was filtered, the solvent was removed and the residue was purified by chromatography to give 36 mg of the title compounds.
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)C(=O)OC(C)(C)C)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([NH:3][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([OH:33])([C:29]([F:30])([F:32])[F:31])[C:25]([F:27])([F:28])[F:26])=[CH:22][CH:23]=2)[CH2:15][CH2:16]1)[CH3:2]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 20 h
Yield: 98.4 %

Procedure:
A mixture of tert-butyl ethyl(1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperidin-4-yl)carbamate (6.61 mmol, 3.2 g), dichloromethane (10 mL) and trifluoroacetic acid (10 mL) was stirred for 20 hours. Purification by SCX chromatography gave the title compound (2.5 g). MS (ESI) m/z 385.1 [M+H]+
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2].[CH3:17]C1N=CC=C2C=NNC=12>>[C:1]([C:4]1[C:12]2[C:7](=[C:8]([CH3:17])[N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2]
Reactant: Cc1nccc2cn[nH]c12
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Product: Cc1nccc2c(C(N)=O)nn(CC(=O)O)c12

Procedure:
was prepared using the same procedure as for the preparation of 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid starting from 7-methyl-1H-pyrazolo[3,4-c]pyridine (Scheme A26). MS (LC-MS): 235 [M+H]+, tR (HPLC conditions k): 0.6 min.
Reaction SMILES: [O:1]=[C:2]1[C@H:6]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][C:4](=[O:18])[O:3]1.[BH4-].[Na+]>C1COCC1>[CH2:10]([O:9][C:8]([NH:7][C@@H:6]([CH2:2][OH:1])[CH2:5][C:4]([OH:18])=[O:3])=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1C[C@@H](NC(=O)OCc2ccccc2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
A solution of (R)-benzyl 2,5-dioxotetrahydrofuran-3-ylcarbamate (INTERMEDIATE 1, 53.28 g, 213.79 mmol) in THF (330 ml) was added over a 4 hour period using an additional funnel to a mixture of sodium borohydride (8.09 g, 213.79 mmol) in THF (330 ml) at 0° C. After the addition was complete, the mixture was warmed to room temperature and stirred for 2 hours. The solution was then concentrated under reduced pressure to ¼ of the original volume, cooled to 0° C., and carefully quenched by the slow addition of water (400 ml). The mixture was acidified to pH 4 with 1N aqueous hydrochloric acid and extracted with Et2O (5×300 ml). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to provide the title product (45.9 g, yield: 85%).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl>C(O)CCCCC>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH2:38][CH2:3][CH2:4][CH2:5][CH3:6])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CCCCCCO
Product: CCCCCCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Temperature: 25 °C
Reaction time: 19 h
Yield: 53 %

Procedure:
0.60 g (1.1 mMol) of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride were added to about 30 ml of n-hexanol saturated with hydrogen chloride and the mixture was stirred for 19 hours at room temperature. Then the hexanol was distilled off in vacuo, the residue was mixed with about 5 ml of 1N ammonia solution with stirring and evaporated down once more. The crude product thus obtained was purified by column chromatography (silica gel, dichloromethane/methanol=5:1). Yield: 53 % of theory, C31H37N7O3 (555.7) Rf value: 0.36 (silica gel; dichloromethane/methanol =5:1) EKA mass spectrum: (M+H)+ =556