Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](OB(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].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.C1(C)C=CC=CC=1>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][NH:8][CH2:9]3)=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Reactant: Cc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc3c(c2)CNCC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To 7-bromo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (8.1 g), 4-methylphenylboric acid (3.9 g), a 2 M aqueous solution of potassium carbonate (40 ml) and ethanol (40 ml) was added toluene (100 ml), and the resulting mixture was stirred at room temperature under an argon atmosphere for 30 minutes. Thereto was added tetrakis(triphenylphosphine)palladium (1.26 g), and the resulting mixture was refluxed under an argon atmosphere for 4.5 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, methanol (200 ml) and a 2 M aqueous solution of potassium carbonate (50 ml) were added to the residue, and the resulting mixture was stirred overnight at room temperature. After concentration, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and was then back-extracted with 1 N hydrochloric acid. The aqueous layer was made alkaline with a 1 N aqueous solution of sodium hydroxide, was then saturated with sodium chloride and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline (4.2 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([I:12])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:13][O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[I:12]
Reactant: Cc1cc(Cl)cc(I)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1c(C)cc(Cl)cc1I
Temperature: 70 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
A solution of 4-chloro-2-iodo-6-methyl-benzoic acid (5.9 g, 20.0 mmol) in acetone (50 mL) was treated with anhydrous K2CO3 (4.14 g, 30 mmol) followed by methyl iodide (1.5 g, 24 mmol). The reaction mixture was stirred at 70° C. for 2 h. GC-MS and TLC indicated that the reaction was completed. The solids were removed by filtration and the filtrate was evaporated under reduced pressure. Silica gel column chromatography of the resulting material using 10% ethyl acetate in hexanes afforded 4-chloro-2-iodo-6-methyl-benzoic acid methyl ester (2.91 g, 47%). GC-MS: m/z 310 (M)+, 279 (M−31)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:16])[C:10](=[CH2:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([NH:31][CH2:15][CH:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[OH:16])[C:11]([O:13][CH3:14])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: C=C(C(=O)OC)C(O)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 2-[(3,4-dichlorophenyl)(hydroxy)methyl]prop-2-enoate (13.6 g) and triethylamine (8.74 mL) in methanol (100 mL) was added benzylamine (6.84 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (4.17 g).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:6][C:7]1[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=1[O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[C:25]([F:26])=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][N:17]=2)[CH2:11]1)[CH3:5]>O1CCCC1.O>[CH2:4]([O:6][C:7]1[CH:30]=[CH:29][CH:28]=[CH:27][C:8]=1[O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[C:25]([F:26])=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=2)[CH2:11]1)[CH3:5]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)OC)cc2F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cc2F)C1
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
Lithium hydroxide hydrate (62 mg, 2.6 mmol) was added to a solution of methyl (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinate (0.65 g, 1.7 mmol) in tetrahydrofuran (8 mL) and water (8 mL), and the resulting solution was stirred at 20-25° C. for 18 h. The mixture was then diluted with water (20 mL) and was washed with ethyl acetate (2×30 mL). The aqueous layer was acidified with citric acid solution (pH-2) and was extracted with ethyl acetate (3×30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to afford (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoronicotinic acid as a white solid (0.50 g). 1H NMR (400 MHz, DMSO-d6) δ 12.85 (br s, 1H), 8.46 (s, 1H), 7.68 (dd, 1H), 7.00 (dd, 1H), 6.87 (m, 3H), 4.39 (m, 1H), 4.02 (dd, 1H), 3.89 (m, 2H), 3.68 (m, 3H), 1.97 (m, 2H), 1.79 (m, 1H), 1.55 (m, 1H), 1.22 (t, 3H). MS (ES+) 361.2 (M+H).
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:2][CH3:3])[CH:6]=1
Reactant: CCI
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Iodoethane (0.46 mL, 0.0058 mol) was added to a suspension of 3-bromothiophenol (0.50 mL, 0.0048 mol), ACN (7.11 mL, 0.136 mol) and potassium carbonate (2.0 g, 0.014 mol). The reaction was stirred for 2 h at rt, was diluted with ethyl acetate and filtered to remove the solids. The reaction was concentrated in vacuo to give 1-bromo-3-(ethylthio)benzene as a colorless oil 1.0 gm, 100%
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16][CH2:17]O>C(Cl)Cl.CN(C=O)C>[CH2:16]([O:5][C:4](=[O:6])[C:3]1[C:2]([Cl:1])=[CH:10][N:9]=[CH:8][C:7]=1[Cl:11])[CH3:17]
Reactant: CCO
Reactant: O=C(O)c1c(Cl)cncc1Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(Cl)cncc1Cl
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 3,5-dichloroisonicotinic acid (52 mmol) in 250 mL DCM and 5 mL DMF were added 11.4 mL thionylchloride. The mixture was heated to 40° C. for 2.5 h, cooled to RT before 100 mL EtOH were added. The solution was stirred at RT for 10 min and then concentrated in vacuo. The crude mixture was taken up in EtOAc and quenched with sat. aq. NaHCO3 solution under ice cooling. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by CC using Hept/EtOAc (95/5 to 85/15) gives the desired product as colorless oil;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:30][C:29]1[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=1)[N:6]=[C:5]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)Cc1n[nH]c2ccc(F)cc12
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2ccc(F)cc12
Temperature: 25 °C
Yield: 38.2 %

Procedure:
Ethyl 2-(5-fluoro-1H-indazol-3-yl)acetate (0.48 g, 2.16 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). Cesium carbonate (2.11 g, 6.48 mmol) was added, and stirred at room temperature for half an hour. Then p-nitro benzyl bromide (466 mg, 2.16 mmol) was added. After reacted for 16 hours, the solid was filtered. The filtrate was concentrated, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a yellow solid 295 mg, at a yield of 38.2%.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[C:6]1=NN(C)C.C(OCC)(=[O:25])C>O1CCCC1.P([O-])([O-])([O-])=O.O.O.[Cu](Cl)Cl>[CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[C:6]1=[O:25]
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)C(=NN(C)C)C(CC(OC)OC)CC2
Agent: Cl[Cu]Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(CC(OC)OC)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,2,3,4-Tetrahydro-1-(dimethylhydrazono)-7-methoxy-2-naphthaleneacetaldehyde dimethyl acetal (45.0 g) was dissolved under argon in a mixture of 1800 ml of tetrahydrofuran and 645 ml of 0.067M phosphate buffer of pH value 7. The solution was treated with 19.8 g of copper(II) chloride dihydrate and stirred at room temperature for 16 hours. 1000 ml of ethyl acetate were added to the reaction mixture and it was washed three times with 1500 ml of a mixture of 25% ammonia solution and saturated ammonium chloride solution (1:19) each time. The aqueous wash phases were extracted twice with 1000 ml of ethyl acetate, the organic phases were combined, dried over MgSO4 and freed from solvent. There were obtained 39.7 g of crude 1,2,3,4-tetrahydro-7-methoxy-1-oxo-2-naphthaleneacetaldehyde dimethyl acetal which was processed without purification.
Reaction SMILES: Cl[C:2]1[C:3]([CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C>O1CCOCC1>[CH:17]1([C:3]2[C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:7][N:6]3[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: c1ccc(-c2nnc3cc(C4CCC4)c(N4CCOCC4)nn23)cc1

Procedure:
6-Chloro-7-cyclobutyl-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (100 mg, 0.35 mmol), morpholine (154 mg, 1.8 mmol) and triethylamine (178 mg, 1.8 mmol) were heated in 1,4 dioxane (6 ml) in a sealed tube at 90° C. for 24 h. The reaction mixture was partitioned (ethyl acetate/water). The organic layer was washed (water, brine), dried (MgSO4) and was evaporated in vacuo. The residue was purified by chromatography on silica gel, eluting with ethyl acetate to give the title compound. 1H NMR (250 MHz, CDCl3) δ 1.96-2.88 (1H, m), 2.48 (2H, m), 3.25-3.28 (4H, m), 3.70-3.76 (1H, m), 3.90-3.94 (4H, m), 7.52-7.55 (3H, m), 7.98 (1H, s), 8.49 (2H, s); MS (ES+) m/e 336 [MH]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[CH:12].[CH:13]1([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=2)(=[O:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>CC#N.C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:20])=[O:19])[CH:22]=1
Reactant: C#CCCOCCCCCCBr
Reactant: O=S(=O)(c1cccc(I)c1)C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=S(=O)(c1cccc(C#CCCOCCCCCCBr)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-[(6-bromohexyl)oxy]-1-butyne (DE 3513885 A1) (288.9 mg) and 1-(cyclopentylsulfonyl)-3-iodobenzene (500 mg) in MeCN (20 ml) and triethylamine (345 μl) was treated with copper iodide (11.78 mg) and dichlorobis(triphenylphosphine)palladium(II) (43.4 mg) and stirred at room temperature for 3 h. The reaction mixture was partitioned between EtOAc and water, the organic phase was dried (MgSO4) and concentrated in vacuo. The mixture was purified by column chromatography (SPE bond elut, gradient 0 to 40% diethyl ether in cyclohexane) to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([OH:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1>ClCCl.C(OCC)(=O)C.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:26][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](O)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](OC1CCCCO1)c1ccccc1
Reaction time: 5 h
Yield: 107 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-hydroxy-2-phenylethyl]carbamate (3.20 g) in dichloromethane (40 ml) were added 3,4-dihydro-2H-pyran (1.28 g) and pyridinium p-toluenesulfonate (191 mg) at room temperature and the mixture was stirred at the same temperature for 5 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give tert-butyl [2-(4-bromophenyl)ethyl][(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]carbamate (4.11 g).
Reaction SMILES: OC1C=CC(C(C2C=[CH:15][C:14]([OH:17])=CC=2)(C)C)=CC=1.C1OC1.C1(CN=C=O)C(C[N:28]=[C:29]=[O:30])=CC=CC=1.[C:35]([O:39]CCOC1C=CC=CC=1)(=[O:38])[CH:36]=[CH2:37].C(OCCO)(=O)C=C>>[C:35]([OH:39])(=[O:38])[CH:36]=[CH2:37].[NH2:28][C:29]([O:17][CH2:14][CH3:15])=[O:30]
Reactant: C=CC(=O)OCCOc1ccccc1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=C=NCc1ccccc1CN=C=O
Agent: C=CC(=O)OCCO
Solvent: C1CO1
Product: C=CC(=O)O
Product: CCOC(N)=O

Procedure:
To a reactor, 53.3 parts by mass of bisphenol-A/ethyleneoxide 2 mole-adduct, 34.0 parts by mass of xylylene diisocyanate, and 93.5 parts by mass of phenoxyethyl acrylate were added and reacted at 80° C. for 5 hours; then, 6.2 parts by mass of 2-hydroxyethyl acrylate and 0.03 parts by mass of urethanizing catalyst were added and reacted at 80° C. for 5 hours, to obtain a urethane acrylate-based oligomer (i.e. a light curable oligomer).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:20]([C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][CH:32]=3)=[O:30])[C:19]([C:39]3[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:40]=3[O:49][CH2:50][CH3:51])=[N:18]2)=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH:21]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[N:20]([C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)=[CH:33][CH:32]=3)=[O:30])[C:19]([C:39]3[CH:44]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:42]=[CH:41][C:40]=3[O:49][CH2:50][CH3:51])=[N:18]2)=[CH:13][CH:12]=1
Reactant: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)c1ccc(CCl)cc1
Reactant: OCCN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)c1ccc(CN2CCN(CCO)CC2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(2-Hydroxyethyl)-piperazine (10 uL, 0.08 mmol) was added to a solution of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-chloromethyl-phenyl)-methanone (20 mg, 0.03 mmol) and diisopropylethylamine (7 uL, 0.04 mmol) in anhydrous dimethylformamide (1.0 mL). The mixture was stirred overnight at 80° C. Evaporation of the solvent and chromatography of the residue over silica gel using 1-5% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-{(4-(2-hydroxyethyl)piperazine-1-yl)methyl}phenyl]methanone, which was dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to give [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-{(4-(2-hydroxyethyl)piperazine-1-yl)methyl}phenyl]methanone hydrochloride as a off-white powder (21 mg, 98%). LR-MS (APCI): 726.1 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1cc2nc(Br)cnc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nc(Br)cnc2n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
2-Bromo-6-methyl-5H-pyrrolo[2,3-b]pyrazine (0.300 g, 1.41 mmol) was dissolved in DMF (5 mL) and cooled down to 0° C. NaH (60%, 68 mg, 1.70 mmol) was added slowly. After the addition was complete stirring was continued for 30 minutes at 0° C. (2-Chloromethoxy-ethyl)-trimethyl-silane (0.30 mL, 1.70 mmol) was added and the reaction mixture was allowed to warm up overnight. The reaction was quenched with H2O. The aqueous layer was extracted with EtOAc. The organic layer was dried (MgSO4), filtered, concentrated, and purified by SiO2 chromatography (40 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 340 mg of 2-bromo-6-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine as a yellow liquid (70% yield).
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[NH2:28][C:29]1[C:32](=[O:33])[C:31](=[O:34])[C:30]=1OCC>CO>[ClH:1].[NH2:28][C:29]1[C:32](=[O:33])[C:31](=[O:34])[C:30]=1[NH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CCOc1c(N)c(=O)c1=O
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(N)=Nc1nc(-c2cccc(CNc3c(N)c(=O)c3=O)n2)cs1
Yield: 73.5 %

Procedure:
A mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole trihydrochloride (1.5 g), triethylamine (1.8 ml) and 1-amino-2-ethoxy-1-cyclobutene-3,4-dione (0.65 g) in methanol (30 ml) was heated under reflux for 7 hours. The solvent was removed by concentration in vacuo. To the residue was added a mixture of water and ethyl acetate, and the mixture was adjusted to pH 1.0 with 6N-hydrochloric acid. The isolated precipitate was collected by filtration and dried. The precipitate was recrystallized from an aqueous N,N-dimethylformamide to give 4-[6-(1-amino-3,4-dioxo-1-cyclobuten-2-yl)aminomethylpyridin-2-yl]-2-(diaminomethyleneamino)thiazole hydrochloride (1.17 g).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)=O.[CH3:14][C:15]1([CH3:28])[C@@H:17]2[CH2:18][C:19]3[C:23]([C@H:16]12)=[C:22]([CH3:24])[S:21][C:20]=3[C:25](=[O:27])[CH3:26].[OH-].[K+].Cl>CO.O>[O:27]=[C:25]([C:20]1[S:21][C:22]([CH3:24])=[C:23]2[C:19]=1[CH2:18][C@H:17]1[C:15]([CH3:28])([CH3:14])[C@H:16]12)[CH:26]=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reactant: O=Cc1ccc(CCC(=O)O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1sc(C(=O)C=Cc2ccc(CCC(=O)O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Yield: 41.1 %

Procedure:
A solution of 3-(4-formyl-phenyl)-propionic acid (142 mg, 0.80 mmol), (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (176 mg, 0.80 mmol), KOH (2.8 g, 50 mmol) in methanol (25 mL) is stirred at 70° C. for 1 h. The reaction mixture is diluted with water (400 mL) and acidified by adding 2 N aq. HCl. The mixture is extracted twice with DCM, the organic extracts are combined, dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC (Waters Xterra MS18 30×75 mm, 10 to 95% acetonitrile in water containing 0.5% formic acid) to give 3-{4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenyl]-phenyl}-propionic acid (125 mg) as yellow resin; LC-MS: tR=1.07 min, [M+1]+=381.18.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:25]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=1[F:23]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: COc1ccc(-c2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)c(F)c1
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2-(2-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane were coupled in the same way as in Example 30 to give 2-[3-(2,2′-difluoro-4′-methoxybiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (5 mg, 3%): m/z (ES+) 413 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19](N3CCOCC3)[CH:18]=2)=[C:14]([CH3:16])[N:15]=1)=[O:9])[CH3:2].C(OC(=O)CNC(NC1SC(C2C=CN=CC=2)=C(C)N=1)=O)C>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][C:13]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[C:14]([CH3:16])[N:15]=1)=[O:9])[CH3:2]
Reactant: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)c2)s1
Agent: CCOC(=O)CNC(=O)Nc1nc(C)c(-c2ccncc2)s1
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccncc2)s1

Procedure:
This compound is prepared by an analogous procedure to 3-{3-[4-Methyl-5-(2-morpholin-4-yl-pyridin-4-yl)-thiazol-2-yl]-ureido}-propionic acid ethyl ester (Example 14) by replacing 4-Methyl-5-(2-morpholin-4-yl-pyridin-4-yl)-thiazol-2-ylamine hydrobromide (13b) with 4-methyl-5-pyridin-4-yl-thiazol-2-ylamine (see Example 16 for reference).