Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C@@H:13]([NH:15][C:16]3[N:21]=[C:20]([N:22]4[C@@H:26]([C@@H:27]([OH:29])[CH3:28])[CH2:25][O:24][C:23]4=[O:30])[CH:19]=[CH:18][N:17]=3)[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:40][S:41]([O:29][C@H:27]([C@H:26]1[CH2:25][O:24][C:23](=[O:30])[N:22]1[C:20]1[CH:19]=[CH:18][N:17]=[C:16]([NH:15][C@H:13]([C:10]2[S:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12][CH:11]=2)[CH3:14])[N:21]=1)[CH3:28])(=[O:43])=[O:42]
Reactant: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)O)n1)c1cnc(-c2ccc(Cl)cc2)s1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@H](C)OS(C)(=O)=O)n1)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a round bottom flask with stir bar was added (R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (19 mg, 0.04 mmol) followed by the addition of DCM (1 mL) under nitrogen. Mixture was cooled to 0° C. in a ice/water bath. To this cold solution was added DIEA (0.03 mL, 0.17 mmol) followed by the addition of methanesulfonyl chloride (10 μL, 0.13 mmol). Reaction mixture stirred for 1 hr at 0° C. The reaction mixture was then quenched with water and diluted with DCM. Phases partitioned and the aqueous phase extracted with DCM. Organic layers combined and washed with brine, dried (Na2SO4), filtered and concentrated to afford a orange residue of (S)-1-((R)-3-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-2-oxooxazolidin-4-yl)ethyl methanesulfonate (21 mg, 0.04 mmol, 94% yield). LCMS m/z 524.2 (M+H)+, Rt 0.75 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:22])[O:16][C:15](=[CH:17][C:18](O)=[O:19])[C:14](=[O:21])[O:13]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:18](=[O:19])[CH:17]=[C:15]2[C:14](=[O:21])[O:13][C:12]([CH3:11])([CH3:22])[O:16]2)=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)O)O1
Product: CC1(C)OC(=O)C(=CC(=O)NCCc2ccc(Cl)cc2)O1

Procedure:
By appropriate application of method described in Intermediate 7, 2-(4-chlorophenyl)ethylamine (0.27 mL, 1.9 mmol) and 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-ylidene)acetic acid (365 mg, 2.12 mmol) were converted to Example 241A (190 mg, 32%) as a white solid. HPLC/MS (Method L) RT=1.78 min, [M+1]+ 310.0.
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C:4]1[N:5]2[C:9]([C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:12]=1)=[CH:8][CH:7]=[CH:6]2.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[Cl:31]>C1COCC1>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:28])[F:27])[O:1][N:2]=[C:3]([C:4]3[N:5]4[C:9]([C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:12]=3)=[CH:8][CH:7]=[CH:6]4)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[Cl:31]
Reactant: COC(=O)c1ccc(/C=N/O)n2cccc12
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Temperature: 68 °C
Yield: 10.4 %

Procedure:
A solution of crude (E)-methyl 5-((hydroxyimino)methyl)indolizine-8-carboxylate (300 mg, 1.37 mmol) in THF (20 mL) was added to a stirred solution of DIB (882 mg, 2.74 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (750 mg, 2.74 mmol) in THF (15 mL) at rt. The mixture was heated at 68° C. for 2 h. The solvent was removed under reduced pressure and the crude product was purified by prep-TLC and then Combiflash to give methyl 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylate (70 mg, yield 10%).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH2:5]1[CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]1>O1CCCC1>[CH:8]1([CH:11]([OH:12])[CH:1]=[CH2:2])[CH2:9][CH2:10][CH2:5][CH2:6][CH2:7]1
Reactant: O=CC1CCCCC1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.1 %

Procedure:
To 140 ml of dry tetrahydrofuran, degassed and flushed with nitrogen (3×) and cooled to 0° C. under nitrogen, was added 1.3M vinyl magnesium bromide (195 ml, 253.5 mmol) in tetrahydrofuran rapidly and dropwise over 5 minutes. The resulting solution was stirred for 5 minutes at 0° C. under nitrogen after which a solution of 24.0 g (223 mmol) of cyclohexylcarboxaldehyde in 40 ml of dry tetrahydrofuran was added via syringe at 0° C. The resulting mixture was stirred for 3.75 hours at 0° to 5° C. under a nitrogen atmosphere after which the reaction was quenched at 0° C. by careful addition of saturated aqueous ammonium chloride. The resulting suspension was poured into 1 L of ice cold, saturated, aqueous ammonium chloride and extracted with ethyl acetate. The ethyl acetate extracts were combined and washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, then with brine. The ethyl acetate extract was dried over magnesium sulfate, filtered, and concentrated at room temperature to give 31.0 g of 1-cyclohexyl-prop-2-enol.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[NH:11][C:12](=[O:15])[CH2:13][CH3:14]>C1C=CC=CC=1>[C:12]([NH:11][C:10]1[CH:9]=[C:8]([CH:18]=[CH:17][CH:16]=1)[NH:7][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])(=[O:15])[CH2:13][CH3:14]
Reactant: C=C1CC(=O)O1
Reactant: CCC(=O)Nc1cccc(N)c1
Solvent: c1ccccc1
Product: CCC(=O)Nc1cccc(NC(=O)CC(C)=O)c1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
42 g of diketene were added to a solution of 82.1 g of m-aminopropionanilide in 400 ml of benzene and the mixture was stirred for 41/2 hours and then was vacuum filtered. The recovered precipitate was washed with benzene, then isopropyl ether and dried to obtain 118 g of m-propionamido-acetylacetanilide melting at 70° C. which was used as is for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[C:14]2[N:15]([N:19]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:21]=2)[CH:16]=[CH:17][CH:18]=1.Cl[CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:11])([F:10])[F:12])=[CH:5][C:4]=1[C:13]1[C:14]2[N:15]([N:19]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(C4CCNCC4)cc3)nc12
Reactant: CN(C)C(=O)CCl
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(C4CCN(CC(=O)N(C)C)CC4)cc3)nc12

Procedure:
2-(4-{4-[8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.150 g, 0.321 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.049 mL, 0.481 mmol) in a manner analogous to Example 313 to give product (0.060 g, 34%). MP=109-112° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.55 (s, 1H), 8.79 (d, 1H), 7.95 (s, 1H), 7.82 (d, 1H), 7.62 (d, 1H), 7.55 (d, 2H), 7.35 (d, 1H), 7.05 (m, 3H), 3.85 (s, 3H), 3.15 (s, 2H), 3.05 (s, 3H), 2.95 (m, 2H), 2.82 (s, 3H), 2.40 (m, 1H), 2.10 (m, 2H), 1.65 (br m, 4H): MS=553 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=O)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:17][C:16]1[N:18]=[C:19]([CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:12]2[C:13]=1[CH:14]=[N:15][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N:11]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)C3CCOCC3)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(C4CCOCC4)n3n2)cc1
Yield: 44.8 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]tetrahydro-2H-pyran-4-carboxamide (Intermediate 50) (81 mg, 0.23 mmol), 1,2-dichloroethane (4.5 mL) and phosphorus oxychloride (0.169 mL, 1.81 mmol), to afford 5-methyl-N-[4-(methyloxy)phenyl]-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-2-amine (35 mg) as a yellow solid. MS m/z 340 (M+1).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][OH:10])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:11]1([NH:14][C:15](=[O:41])[C:16]2[CH:21]=[C:20]([F:22])[C:19]([CH3:23])=[C:18]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30](=[O:34])[N:29]([CH2:35][CH:36]3[CH2:38][CH2:37]3)[CH:28]=[C:27]4[CH:39]=O)[CH:17]=2)[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl>[CH:11]1([NH:14][C:15](=[O:41])[C:16]2[CH:21]=[C:20]([F:22])[C:19]([CH3:23])=[C:18]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30](=[O:34])[N:29]([CH2:35][CH:36]3[CH2:37][CH2:38]3)[CH:28]=[C:27]4[CH2:39][N:4]3[CH2:5][CH2:6][CH2:7][N:1]([CH2:8][CH2:9][OH:10])[CH2:2][CH2:3]3)[CH:17]=2)[CH2:12][CH2:13]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: OCCN1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCCN(CCO)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(1,4-Diazepan-1-yl)ethanol (311 mg) was added to a suspension of the product of Example 75 step i) (301 mg) in dichloromethane (5 mL). The reaction was stirred at room temperature for 1 hour before the addition of sodium triacetoxyborohydride (457 mg). The reaction was then stirred at room temperature for 1 hour. The reaction mixture was treated with methanol (2 mL) and then concentrated to dryness. The resulting material was purified by HPLC then by SCX ion exchange chromatography (eluting with methanol followed by 1.5M methanolic ammonia). The fractions containing product were concentrated to dryness and the residue triturated with acetonitrile to afford the title compound as a solid (300 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1)=[O:4].C(=O)([O-])O.[Na+].Cl[CH2:18][CH:19]=O>CO.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:18]=[CH:19][N:11]=[C:7]2[CH:6]=1)=[O:4]
Reactant: O=CCCl
Reactant: COC(=O)c1ccnc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccn2ccnc2c1
Yield: 38 %

Procedure:
A solution of crude 2-aminopyridin-4-ylcarboxylic acid methyl ester (13.0 g) in methanol (150 ml) was treated with sodium hydrogencarbonate (14.3 g, 0.171 mol) and chloroacetaldehyde (8 ml of a 45 wt % solution in water) then heated at reflux for 16 h. The reaction was cooled and pre-adsorbed directly on to silica gel. Purification by flash chromatography eluting with dichloromethane (+1% conc. ammonia) on a gradient of methanol (1%-4%) gave a solid which was triturated with 5% ether in isohexane to afford imidazo[1,2-α]pyridine-7-carboxylic acid methyl ester (8.0 g, 38% from pyridine N-oxide) as a tan solid. 1H NMR (400 MHz, CDCl3) δH 3.97 (3H, s), 7.37-7.43 (2H, m), 7.70 (1H, s), 7.80 (1H, s), 8.18 (1H, dd, J 1 and 7), 8.38 (1H, s).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:13]=[N:14][N:15]=2)[C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:6][N:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17]1>C(O)C>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:5]1[N:4]2[CH:13]=[N:14][N:15]=[C:3]2[C:2]([N:16]2[CH2:19][CH:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:17]2)=[N:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: Clc1ncc(-c2cccs2)n2cnnc12
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CN(c2ncc(-c3cccs3)n3cnnc23)C1
Yield: 31.7 %

Procedure:
A 50 mL round bottom flask was charged with 8-chloro-5-(thiophen-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine (0.25 g, 1.1 mmol), tert-butyl azetidin-3-ylcarbamate (540 mg, 3.1 mmol) and ethanol (5 mL). The resulting solution was refluxed overnight. Work-up: the solvent was evaporated. The residue was purified by flash column chromatography on silica gel with a 1:2 EtOAc/petroleum ether and then a 1:50 methanol/dichloromethane, to afford 130 mg (33%) of the product as a white solid. MS m/z: 373 (M+H+).
Reaction SMILES: O[C@H:2]([CH3:22])[C@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@@H:3]2[C:4](=[O:6])[O:5][C@@H:2]2[CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@@H](O)[C@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1OC(=O)[C@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 69.4 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2S,3R)-3-hydroxy-2-(5-phenylpentoxy-carbonylamino)-butanoic acid (0.3 g, 0.89 mmol) in dry CH2Cl2 (30 mL), Et3N (0.37 mL, 2.67 mmol) and subsequently TBTU (0.34 g, 1.06 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy:EtOAc (from 100:0 to 0:100) to afford the title compound (0.18 g, 70%), as white solid. [α]25D +21.3 (c 0.1, CHCl3). MS (ESI) m/z: 292 [M−H]+; (ESI) m/z: 290 [M−H]−. 1H NMR (DMSO-d6) δ 1.37-1.28 (m, 2H), 1.33 (d, J=6.4 Hz, 3H), 1.64-1.53 (m, 4H), 2.57 (t, J=7.7 Hz, 2H), 4.06-3.93 (m, 2H), 4.84 (dq, J=6.1, 6.4 Hz, 1H), 5.40 (dd, J=6.1, 9.4 Hz, 1H), 7.30-7.13 (m, 5H), 8.19 (d, J=9.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:18][CH3:19])[CH:3]=1.[CH2:20]1[O:31][C:30]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]=2[O:21]1>C(Cl)(Cl)Cl>[CH2:14]([N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][NH:8][C:6]([C:5]1[C:4]([O:18][CH3:19])=[CH:3][C:2]([NH:1][C:25]([C:24]2[CH:28]=[CH:29][C:30]3[O:31][CH2:20][O:21][C:22]=3[CH:23]=2)=[O:26])=[CH:17][CH:16]=1)=[O:7])[CH3:15]
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: CCN(CC)CCNC(=O)c1ccc(N)cc1OC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNC(=O)c1ccc(NC(=O)c2ccc3c(c2)OCO3)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
200 mg (0.75 mmol) of 4-amino-N-(2-diethylamino-ethyl)-2-methoxy-benzamide in 10 ml of chloroform is mixed with 5 ml of 3,4-methylenedioxybenzoic acid chloride (in chloroform) and this mixture is stirred for 3 hours at room temperature. After concentration by evaporation in a vacuum, the residue is taken up in 40 ml of dilute sodium bicarbonate solution and then extracted with 40 ml of methylene chloride. The methylene chloride phase is washed with water, dried, filtered and concentrated by evaporation. The crude product, 315 mg, is taken up in methylene chloride and purified on silica gel. As a mobile solvent, a mixture that consists of methylene chloride/methanol (977:3→90:10) is used. 210 mg (67% of theory) of benzo[1,3]dioxole-5-carboxylic acid [4-(2-diethylamino-ethylcarbamoyl)-5-methoxy-phenyl]-amide (melting point 131.1° C.) is obtained.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([I:24])=[CH:19][N:18]=1.[Cl-].[Na+]>C(OCC)C>[CH2:1]([O:8][C@H:9]([CH3:13])[C@@H:10]([CH3:11])[O:12][C:19]1[C:20]([I:24])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O)[C@@H](C)OCc1ccccc1
Reactant: Clc1ncc(I)c(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1I
Reaction time: 0.17 h
Yield: 41 %

Procedure:
(2R,3R)-3-Benzyloxybutan-2-ol in diethyl ether were admixed with sodium hydride in portions at 0° C. with stirring. After 10 minutes, the ice bath was removed and the mixture was stirred for a further 3 minutes at room temperature. The suspension formed was added, at 0° C., to a solution of 2,4-dichloro-5-iodopyrimidine. The mixture was stirred for 4 hours at 40° C. and then admixed with dilute sodium chloride solution. The mixture was extracted with acetic ester (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified by means of chromatography (hexane/acetic ester 4:1) (yield: 41%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.[OH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2>>[CH:19]1[C:20]2[C:15](=[C:14]([O:13][CH2:2][C:3]3[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)[CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1cccc2cnccc12
Product: O=C(O)c1ccc(COc2cccc3cnccc23)cc1

Procedure:
Methyl 4-(bromomethyl)benzoate was alkylated with commercially available 5-hydroxyisoquinoline using the analogous procedure as used for Example 202. MS found: (M+H)=280.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]([OH:10])=[N:3][CH:2]=1.[Br:11]Br.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:11][C:8]1[S:7][C:6]2[N:1]=[CH:2][N:3]=[C:4]([OH:10])[C:5]=2[CH:9]=1
Reactant: BrBr
Reactant: Oc1ncnc2sccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ncnc2sc(Br)cc12
Temperature: 80 °C

Procedure:
To a solution of thieno[2,3-d]pyrimidin-4-ol (3.0 g, 20 mmol) in glacial acetic acid (40 mL) was added bromine (6.3 g, 39 mmol). After heating to 80° C. for 1.5 hours, the reaction mixture was cooled to room temperature and poured into saturated NaHCO3 and ice. The solid was filtered, washed with water and dried to provide the product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[O:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[NH:20][C:21]([N:4]1[CH2:5][CH2:6][NH:1][CH:2]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3]1)=[O:22]
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C1CNCCN1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CN(C(=O)Nc2cc(Cl)cc(Cl)c2)CCN1
Reaction time: 8 h
Yield: 26.9 %

Procedure:
To a solution of ethyl 2-piperazinecarboxylate (0.9 g, 5.7 mmol) in chloroform (11 mL) was added 3,5-dichlorophenyl isocyanate (1.05 g, 5.7 mmol). The reaction was stirred overnight after which time a precipitate had formed. The reaction was concentrated and the solid was chromatographed on silica gel using ethyl acetate as eluant to provide 0.53 g (27%) of ethyl 4-[(3,5-dichloroanilino)carbonyl]-2-piperazinecarboxylate as an off white powder. Electrospray Mass Spec 346.1 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13]C=C[N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:20]=2)[CH:4]=1.BrC1C=C(C2C=C(C3C=CN(C)N=3)N=C(NC)C=2)[CH:36]=[N:37]C=1>>[CH3:1][NH:2][C:3]1[CH:4]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:20]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][N:37]([CH3:36])[N:10]=2)[N:8]=1
Reactant: CNc1cc(-c2cncc(Br)c2)cc(-c2ccn(C)n2)n1
Reactant: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccccn2)n1
Product: CNc1cc(-c2cncc(-c3cnn(C4CCNCC4)c3)c2)cc(-c2ccn(C)n2)n1

Procedure:
This compound is prepared analogously to Methyl-[5″-(1-piperidin-4-yl-1H-pyrazol-4-yl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.183) by replacing (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (Example 2.1; step1) by [5-Bromo-6′-(1-methyl-1H-pyrazol-3-yl)-[3,4′]bipyridinyl-2′-yl]-methyl-amine (Example 2.178, step 1).
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]2[O:14][CH:15]=[CH:16][N:17]=2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[O:14][CH:15]=[CH:16][N:17]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ncco1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCSc1ncco1

Procedure:
Hydrazine hydrate (5.3 g.) was added carefully to a solution of 2-(3-phthalimidopropylthio)oxazole (10 g.) in ethanol (173 ml.) with stirring. The solution was then heated under reflux for 25 minutes. After cooling, and filtration from phthalhydrazide, the filtrate was concentrated under reduced pressure and the residue was re-evaporated with ethanol to yield crude 2-(3-aminopropylthio)oxazole which was washed twice with ether and dissolved in ethanol (60 ml.). Methyl isothiocyanate (2.54 g.) was added and the solution was heated under reflux for 30 minutes. Following cooling and filtration from insoluble material, the filtrate was concentrated to an oil which was chromatographed on a column of silica gel with ethyl acetate as eluant. The product obtained crystallised from ethanol-ether-n-hexane to give N-methyl-N'-[3-(2-oxazolyl)-thiopropyl]thiourea (2.4 g.), m.p. 43°-45°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.C(OC(CC1C2SC=CC=2C(O[CH2:38][CH2:39][C:40]2[N:41]=[C:42]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=3[O:53][CH2:54][CH3:55])[O:43][C:44]=2[CH3:45])=CC=1)C(O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([O:15][CH2:38][CH2:39][C:40]2[N:41]=[C:42]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=3[O:53][CH2:54][CH3:55])[O:43][C:44]=2[CH3:45])=[CH:8][CH:7]=1
Reactant: CCOc1cc(F)ccc1-c1nc(CCOc2ccc(CC(OCC)C(=O)O)c3sccc23)c(C)o1
Reactant: CCOC(Cc1ccc(O)c2sccc12)C(=O)OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1cc(F)ccc1-c1nc(CCOc2ccc(CC(OCC)C(=O)OC)c3ccsc23)c(C)o1

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(7-hydroxy-benzo[b]thiophen-4-yl)-propionic acid methyl ester (example 151 a]) was reacted with 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (example 95) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(7-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-4-yl)-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(7-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-benzo[b]thiophen-4-yl)-propionic acid as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH2:21][CH2:22][NH:23][CH:24]3[CH3:29])=[CH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:23]3[CH2:22][CH2:21][C:20]4[C:25](=[CH:26][CH:27]=[CH:28][C:19]=4[C:16]4[CH:17]=[CH:18][O:14][CH:15]=4)[CH:24]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(-c3ccoc3)cccc21
Product: CC1c2cccc(-c3ccoc3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Furan-3-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.