Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]([O:14][CH2:15][C:16]([OH:18])=O)=[O:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C([Cl:22])=O>>[C:1]([O:10][CH2:11][C:12]([O:14][CH2:15][C:16]([Cl:22])=[O:18])=[O:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCC(=O)OCC(=O)OCC(=O)O
Product: CCCCCCCC(=O)OCC(=O)OCC(=O)Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5.6 g (0.022 mole) octanoyl-oxyacetyl-oxyacetic acid, 50 ml hexame were placed in a 250 ml round bottom flask. 2.9 ml (0.03 mole) oxalyl chloride was added in one portion and the reaction stirred at room temperature for 6 hours. The reaction was then heated to 80° C., a distillation head attached with condenser and receiver, and the excess oxalyl chloride and solvent removed at reduced pressure. There remained 4.5 g of light yellow oil. IR spectrum reveals no free -OH and a broad v-c=o absorbance, with maxima at 1815, 1780 and 1755 cm-1.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][CH:16]([OH:19])[CH2:17][CH3:18]>>[CH:16]([O:19][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH2:17][CH3:18])[CH3:15]
Reactant: CCC(C)O
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CCC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
Prepared in analogy to Example A1 (b) from 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) and rac-butan-2-ol. The crude material was purified by preparative HPLC to yield the title compound as a white solid. MS (m/e): 271.4 ([M−H]−, 100%).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].O1CCCC1.[H-].[Na+].[Cl:12][C:13]1[N:18]=[CH:17][CH:16]=[C:15](Cl)[N:14]=1>O>[Cl:12][C:13]1[N:18]=[C:17]([O:4][CH2:3][CH2:2][F:1])[CH:16]=[CH:15][N:14]=1
Reactant: OCCF
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FCCOc1ccnc(Cl)n1
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
2-Fluoroethanol (0.30 mL, 4.95 mmol) was added to an anhydrous tetrahydrofuran (5 mL) solution containing sodium hydride (60% NaH, 200 mg, 4.95 mmol), and an anhydrous tetrahydrofuran (5 mL) solution having 2,4-dichloropyrimidine (104, 500 mg, 3.30 mmol) dissolved therein was slowly added. The reaction mixture was stirred for 30 minutes and water was added. Organic compounds were extracted with ethyl acetate. Then, the recovered organic solution was washed with an aqueous solution of saturated sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give 2-chloro-4-(2-fluoroethoxy)pyrimidine (106a, 237 mg, 41%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:11][O:10]2)[CH:6]=[CH:7][CH:8]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:10][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1cccc(C2CO2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cccc(C(O)COc2ccc(C=O)cc2)c1
Temperature: 78 °C
Yield: 122 %

Procedure:
To a stirring solution of 2-(3-methoxyphenyl)oxirane (5.60 g, 37.0 mmol) in toluene (65 ml) was added 4-hydroxybenzaldehyde (6.80 g, 5.60 mmol), 1M NaOH (65 ml) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. overnight. The reaction mixture was allowed to cool to RT and extracted with EtOAc (2×150 ml). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed, eluting with 30-40% EtOAc/hexanes. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.86 g (18%) of the title compound as a clear colorless oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.90 g (9%) the regioisomer as a nearly colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[OH:36]>>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH3:10])[N:7]=2)[CH:24]=[CH:23][C:22]=1[OH:36]
Reactant: COc1ccc([C@H](C)Nc2cncc(Cl)n2)cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1ccc([C@H](C)Nc2cncc(-c3ccc(O)c(OC)c3)n2)cc1
Yield: 35.4 %

Procedure:
In a procedure analogous to Example 2, reaction of 6-chloro-N-[(15)-1-(4-methoxyphenyl)ethyl]pyrazin-2-amine (149.4 mg, 0.57 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (156 mg, 0.62 mmol) furnished the product (71 mg, 35%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:17][C:18](=[O:27])[C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([CH3:16])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][O:37][CH2:38][CH2:39]Br>C(#N)C>[CH3:16][CH:12]([CH2:13][CH2:14][CH3:15])[CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C@@H:3]([NH:17][C:18](=[O:27])[C@H:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20])[CH2:2][N:1]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:9][CH:8]=1
Reactant: CCCC(C)COc1ccc([C@H](CN)NC(=O)[C@@H](C)c2ccccc2)cc1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(C)COc1ccc([C@H](CN2CCOCC2)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a mixture of (2S)-N-((1R)-2-amino-1-(4-(2-methylpentyloxy)phenyl)ethyl)-2-phenylpropanamide (100 mg, 0.271 mmol), prepared according to the procedure described in example 5, and potassium carbonate (75 mg, 0.543 mmol) in acetonitrile (4 mL) was added 2-bromoethyl ether (0.038 mL, 0.271 mmol). The reaction mixture was then heated at reflux for 18 h. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was then transferred to a separatory funnel containing water (20 mL) and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by HPLC (acetonitrile/water with 0.1% TFA) to afford (2S)-N-((1R)-1-(4-(2-methylpentyloxy)phenyl)-2-morpholinoethyl)-2-phenylpropanamide.TFA (55 mg, 37% yield) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.25-7.39 (m, 5H), 6.97 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 6.36 (br. s., 1H), 4.83 (d, J=5.0 Hz, 1H), 3.74 (dd, J=8.8, 5.8 Hz, 1H), 3.61-3.69 (m, 2H), 3.49-3.61 (m, 4H), 2.34-2.56 (m, 4H), 2.23-2.30 (m, 2H), 1.83-1.95 (m, 1H), 1.52 (d, J=7.3 Hz, 3H), 1.26-1.50 (m, 3H), 1.12-1.22 (m, 1H), 0.97 (d, J=6.8 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 439.3 [(M+H)+, calcd for C27H39N2O3 439.3].
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([O:13][CH2:14][CH3:15])(=[O:12])[CH:9]([CH3:11])[CH3:10].Br[CH2:17][CH2:18][Cl:19].[Cl-].[NH4+]>O1CCCC1>[Cl:19][CH2:18][CH2:17][C:9]([CH3:11])([CH3:10])[C:8]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: ClCCBr
Reactant: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCl
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 22.2 ml of diisopropylamine in 150 ml of tetrahydrofuran was added 93.6 ml of 1.6M n-butyllithium-hexane with stirring at -5° to 0° C. and the mixture was stirred for 30 minutes. The reaction mixture was cooled to -78° C. and 19.0 ml of ethyl isobutyrate was added dropwise. The mixture was then further stirred for 45 minutes, after which a solution of 11.9 ml of 1-bromo-2-chloroethane in 10 ml of tetrahydrofuran was added dropwise. The reaction mixture was stirred at -78° C. for 1 hour and, then, at room temperature for 2 hours. After an excess amount of an aqueous solution of ammonium chloride was added, the mixture was extracted with ethyl acetate. The extract was washed with water and dried (MgSO4) and the solvent was distilled off. Finally, the residue was distilled under reduced pressure to provide 24.7 g of the title compound as colorless oil. b.p. 54°-56° C./0.25 mmHg
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][CH:41]([C:44]([NH2:46])=[O:45])[CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:38]3[CH2:43][CH2:42][CH:41]([C:44]([NH2:46])=[O:45])[CH2:40][CH2:39]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC(=O)C1CCNCC1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperidine-4-carboxylic acid amide (isonipecotamide, Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H34N4O3F3Cl2 [(M+H)+] 661.1955, observed 662.1955.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH:20]=O)=[CH:12]1.C(OC(=O)C)(=O)C.CCN(CC)CC>>[NH:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH:20]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([OH:10])=[O:9])=[CH:12]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: O=C(O)Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 44.3 %

Procedure:
A mixture of phenylacetic acid (0.0376 mol., 5.1 g) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (0.0376 mol., 5.5 g) in acetic anhydride (0.1881 mol., 17.7 ml) and Et3N (0.0376 mol., 5.2 ml) was stirred at 100° C., for 6 hrs. The obtained solution was cooled to 50° C., quenched with conc. hydrochloric acid (10 ml) and extracted with EtOAc. The organic phase was extracted with 1 N NaOH. 3-(1H-Pyrrolo[2,3-b]pyridin-3-yl) -2-phenyl-2-propenoic acid was then precipitated from the aqueous layer with conc. hydrochloric acid with ice-cooling. Filtration and recrystallization from isopropyl alcohol of the crude product afforded 4,4 g of the desired compound as a white solid (44%), m.p. >230° C.
Reaction SMILES: CON(C)[C:4](=[O:20])[CH:5]([O:18][CH3:19])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([CH3:17])=[N:15][N:16]=2)=[CH:8][CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=[C:28]([O:31][CH3:32])[C:29]=1[CH3:30]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:33]2[O:34][C:35]([C:4](=[O:20])[CH:5]([O:18][CH3:19])[C:6]3[CH:7]=[CH:8][C:9]([C:12]4[O:13][C:14]([CH3:17])=[N:15][N:16]=4)=[CH:10][CH:11]=3)=[CH:36][CH:37]=2)[CH:27]=[C:28]([O:31][CH3:32])[C:29]=1[CH3:30]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1C
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(OC)c1C
Yield: 29 %

Procedure:
N,2-Dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide was reacted with 2-(3,5-dimethoxy-4-methylphenyl)furan according to the procedure used for the synthesis of Example 12. Purification by chromatography (EtOAc-hexanes) gave 1-(5-(3,5-dimethoxy-4-methylphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone as a yellow foam (0.148 g, 29% yield). MS: m/z 449.2 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O.[CH3:21][N:22](C=O)[CH3:23]>>[F:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH2:15][CH2:16][CH2:17][C:18]([N:22]([CH3:23])[CH3:21])=[O:20]
Reactant: CN(C)C=O
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1F
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)CCCc1ccc([N+](=O)[O-])cc1F
Temperature: -5 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Thionyl chloride (0.01 mL, 0.11 mmol) was added slowly to a solution of 4-(2-Fluoro-4-nitrophenyl)butanoic acid (82) (18 mg, 0.08 mmol) in DMF (3 mL) cooled at −5° C. The mixture was stirred for an additional 1 h at −5° C. Excess dimethylamine (freshly distilled from its 40% aqueous solution) was added to the reaction medium. The second mixture was stirred for an additional 1 h. Ethyl acetate (30 mL) was added to the mixture, which was washed with brine (2×30 mL). The organic layer was dried over MgSO4, and concentrated to yield 4-(2-Fluoro-4-nitrophenyl)-N,N-dimethylbutanamide (77) (18 mg, 87%): 1H NMR δ 7.98 (dd, 1H, J=8.3, 2.1 Hz), 7.89 (dd, 1H, J=9.5, 2.1 Hz), 7.42 (dd, 1H, J=8.3, 7.4 Hz), 2.98 (s, 3H), 2.95 (s, 3H), 2.81 (t, 2H, J=7.6 Hz) 2.36 (t, 2H, J=7.2 Hz) 1.96-2.04 (m, 2H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1.C[Si]([C:19]#[CH:20])(C)C.N1C=CC=CC=1>C(N(CC)CC)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]#[CH:20])=[CH:10][CH:9]=1
Reactant: Ic1ccc(OCC2OCCO2)cc1
Reactant: C#C[Si](C)(C)C
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(OCC2OCCO2)cc1
Yield: 83 %

Procedure:
1-[(1,3-Dioxolan-2-yl)methyloxy]-4-iodobenzene (36.3 g) and trimethylsilylacetylene (50.0 g) were reacted in the presence of bistriphenylphosphinepalladium dichloride (2.50 g) and cuprous iodide (1.25 g), in triethylamine (140 ml) and pyridine (70 ml) at 60° C. for 2 hr. The reaction solution was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried and concentrated. The resulting residue was dissolved in methanol and treated with 2N sodium hydroxide, to give 20.1 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)=O>ClCCl>[C:2]1([NH:1][C@H:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:27])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)OS(=O)(=O)C(F)(F)F
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)Nc1ccccc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a stirred solution of aniline (4.55 mL, 50 mmol) and triethylamine (7 mL, 50 mmol) in anhydrous dichloromethane (120 mL) was added a solution of ethyl 2-{[(trifluoromethyl)sulfonyl]oxy}propanoate (12.5 g, 50 mmol) in dichloromethane (60 mL) at 0° C. (Ice bath) over a period of 30 minutes under nitrogen. The ice bath was then removed and the reaction mixture was stirred at 35° C. for 2 h. The reaction mixture was cooled to rt, washed with water, dried over sodium sulfate, and evaporated to give desired product as oil (8.9 g, 92%) which was used as such for the next step. 1HNMR (300 MHz, CDCl3): δ 1.19-1.67 (m, 6H), 4.17-4.38 (m, 3H), 6.65-6.80 (m, 3H), 7.20-7.35 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[N:3]=1.C([Si](C(C)C)(C(C)C)[N:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH3:16][N:14]1[CH:15]=[C:11]([C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[CH:25][NH:21][CH:22]=3)[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=2)[CH:12]=[N:13]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Reactant: Cn1cc(-c2cc3nccn3c(Cl)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3nccn3c(-c3cc[nH]c3)n2)cn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 129.6 %

Procedure:
To a flask charged with 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation J; 0.150 g, 0.642 mmol), 1-(triisopropylsilyl)-1H-pyrrol-3-ylboronic acid (0.257 g, 0.963 mmol), and potassium phosphate (0.321 mL, 0.642 mmol) was added 6 mL of dioxane and argon was bubbled through the mixture for 15 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.0742 g, 0.0642 mmol) was added and argon was bubbled through the reaction for 15 minutes. The flask was sealed under argon and the mixture was heated at 75° C. with stirring overnight. The reaction was then concentrated under reduced pressure and then taken up in DCM (5 mL). A precipitate was formed and collected by means of vacuum filtration and washed with DCM (10 mL). The solid contained product without the triisopropylsilyl protection as well as inorganic salts. Further purification was not attempted and so was obtained 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrrol-3-yl)imidazo[1,2-c]pyrimidine (0.220 g, 0.832 mmol, 130% yield). MS (apci) m/z=265.1 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=O)[O:28]C3C=CC=CC=3)=[CH:22][CH:21]=2)[N:9]=1)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].CC([C:43]1C=C(N2CCOC[C@@H]2C)N=C(C2C=CC(NC(=O)OC3C=CC=CC=3)=CC=2)[N:44]=1)(S(C)(=O)=O)C>>[CH3:43][NH:44][C:27](=[O:28])[NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:10]2[N:9]=[C:8]([C:2]([S:4]([CH3:7])(=[O:5])=[O:6])([CH3:3])[CH3:1])[CH:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=2)=[CH:25][CH:24]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: CC(C)(c1cc(N2CCOCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1)S(C)(=O)=O
Product: CNC(=O)Nc1ccc(-c2nc(N3CCOCC3)cc(C(C)(C)S(C)(=O)=O)n2)cc1

Procedure:
The following compounds were prepared in analogous fashion from either phenyl (4-{4-[1-methyl-1-(methylsulfonyl)ethyl]-6-morpholin-4-ylpyrimidin-2-yl}phenyl)carbamate or phenyl (4-{4-[1-methyl-1-(methylsulfonyl)ethyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}phenyl)carbamate and the appropriate amine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36]2[CH:44]=[C:43]3[C:39]([CH2:40][CH2:41][N:42]3[C:45](=[O:47])[CH3:46])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:45]([N:42]1[C:43]2[C:39](=[CH:38][CH:37]=[C:36]([N:35]([CH:32]3[CH2:31][CH2:30][N:29]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:34][CH2:33]3)[C:8](=[O:10])/[CH:7]=[CH:6]/[C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:44]=2)[CH2:40][CH2:41]1)(=[O:47])[CH3:46]
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Reactant: O=C(O)/C=C/c1ccsc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(N(C(=O)/C=C/c3ccsc3)C3CCN(Cc4ccccc4)CC3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a mixture of trans-3-thiophen-3-yl-acrylic acid (66 mg, 0.43 mmol) and oxalyl chloride (45 μL, 0.52 mmol) in 2 mL of CH2Cl2 was added a catalytic amount of DMF. After stirring at rt for 2 h, the mixture was concentrated in vacuo. The resulting crude acid chloride was dissolved in CH2Cl2 and treated with TEA (80 μL, 0.58 mmol) and 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (0.100 g, 0.286 mmol). After stirring for 4 h, the mixture was washed with satd. aq. NaHCO3 followed by brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (60% EtOAc/hexanes) afforded 118 mg (64%) of the title compound. 1H NMR (500 MHz, CDCl3): 8.02 (br s, 1H), 7.83 (d, J=15.7 Hz, 1H), 7.39-7.16 (m, 8H), 6.94-6.93 (m, 1H), 6.73-6.72 (m, 1H), 5.97 (d, J=15.7 Hz, 1H), 4.74-4.70 (m, 1H), 4.17-4.13 (m, 2H), 3.45 (br s, 2H), 3.28-3.23 (m, 2H), 2.88 (br s, 3H), 2.23 (s, 3H), 2.13 (m, 2H), 1.88-1.76 (m, 3H). MS: exact mass calculated for C29H18N3O2, 485.21; m/z found, 486.2 [M+H]+, 508.1 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:19]([O:21][CH2:22][CH2:23]Cl)[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([O:21][CH2:22][CH2:23][O:10][C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:20]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCCOc1cc(C)cc(C)c1C
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 2,3,5-trimethylphenol (3.0 g, 22.0 mmol), potassium carbonate (3.65 g, 26.4 mmol) and potassium iodide (0.55 g, 3.3 mmol) in N,N-dimethylformamide (50 mL) was added 2-chloroethyl ethyl ether (3.59 g, 33.3 mmol) under stirring at room temperature, and the mixture was stirred at 70° C. for 24 hr. To the reaction mixture were added reagents (potassium carbonate, potassium iodide and 2-chloroethyl ethyl ether) in the same amount as mentioned above, and the mixture was further stirred at 70° C. for 24 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=49/1-hexane/ethyl acetate=4/1) to give the title compound (4.1 g, yield 90%) as a colorless oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][C:34](=[O:43])[N:35]3[CH2:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:30][CH:29]=2)=[CH:9][CH:8]=1)#[N:2]>N.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][C:34](=[O:43])[N:35]3[CH2:38][CH2:39][CH2:40][O:41][CH3:42])=[CH:30][CH:29]=2)=[CH:9][CH:8]=1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCC#N)cc3)cc21
Agent: [Ni]
Agent: N
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCN)cc3)cc21

Procedure:
The solution of 0.650 g of tert-butyl 4-[4-(3-cyanopropoxy)phenyl]-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate in 10 ml of ammonia (2M in methanol) is hydrogenated in the presence of 0.65 g of Raney nickel at 45° C. over 3 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The title compound is obtained as a brown oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.13 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=4.18.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13](S(C)(=O)=O)=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])[CH3:3].[C-:25]#[N:26].[Na+].Cl>CN(C)C=O>[CH3:23][C:20]([C:7]1[CH:8]=[C:9]([C:11]2[S:12][C:13]([C:25]#[N:26])=[N:14][N:15]=2)[CH:10]=[C:5]([C:2]([CH3:3])([CH3:4])[CH3:1])[C:6]=1[OH:24])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nnc(C#N)s2)cc(C(C)(C)C)c1O
Temperature: 85 °C
Yield: 45 %

Procedure:
A solution of 0.52 g (1.41 mmol) of methyl sulfone (Example 36) and 0.15 g (3.06 mmol, 2.17 equiv.) of NaCN in 4 ml dimethylformamide is warmed at 65° C. for 25 hours. An additional portion of NaCN is added and the reaction is warmed at 75° C. for 16 hours and 85° C. for one hour. The reaction is poured onto 3N aqueous HCl and extracted with ethyl acetate (three times). The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Flash chromatography (SiO2, 230-400 mesh, 15×4.5 cm, 15% ethyl acetate-hexane) gives 0.20 g of the nitrile. Recrystallization from cyclohexane gives 0.14 g (0.44 g theor., 31%) of the pure nitrile, mp 140°-140.5° C.