Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.BrCC(OCC)=O>[Pd]>[CH:1]1([NH:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NCc1ccccc1
Reactant: O=C1CCc2ccccc21
Agent: [Pd]
Agent: CCOC(=O)CBr
Product: c1ccc(CNC2CCc3ccccc32)cc1

Procedure:
The amino acid was synthesized as described by Miyake, et al., Takeda Kenkyushoho 44: 171-185 (1985). [Chem. Abstr. 106: 156830 (1987)]. N-(1-indanyl)-benzylamine was prepared by reductive amination of 1-indanone with benzylamine, and alkylation of the amine by ethyl bromoacetate. The benzyl group was cleaved by hydrogenolysis over palladium. Saponification of the ethyl ester gave the amino acid, which was converted to the Boc derivative by the standard procedure described in Example III.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cu][C:20]#[N:21].[OH-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[N:21])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: N#C[Cu]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Br)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#N)cc1
Temperature: 170 °C
Yield: 15933 %

Procedure:
A solution of 2-(4-bromo-phenyl)-3-cyclopentyl-propionic acid methyl ester (500 mg, 1.60 mmol) in N,N-dimethylformamide (4.01 mL) was treated with copper(I) cyanide (144 mg, 1.60 mmol). The mixture was heated at 170° C. for 1 h. At this time, the reaction was cooled to 25° C. and poured into aqueous ammonium hydroxide (5 mL). The solution was diluted with water (25 mL) and extracted with ethyl acetate (3×35 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid methyl ester (65.6 g, 15.8%) as a clear oil: EI-HRMS m/e calcd for C16H19NO2 (M+) 257.1415 found 257.1406.
Reaction SMILES: CN1C(C)=C(C(O)=O)C(=O)N1C1C=CC=CC=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:33][C:34]1([CH3:56])[S:38][C@@H:37]2[C@H:39](NC([C@H](N)C3C=CC=CC=3)=O)[C:40](=[O:41])[N:36]2[C@H:35]1[C:53]([OH:55])=[O:54]>CN(C)C=O.CCOCC>[CH3:33][C:34]1([CH3:56])[S:38][C@@H:37]2[CH2:39][C:40](=[O:41])[N:36]2[C@H:35]1[C:53]([OH:55])=[O:54]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Temperature: -10 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
2,3-Dimethyl-1-phenyl-3-pyrazolin-5-one-4-carboxylic acid (0.186 g, 0.8 mmol) in dry dimethyl formamide (D.M.F) (4 ml) was treated with triethylamine (0.12 ml, 0.8 mmol). The solution was cooled to -10° C. and isobutyl chloroformate (0.10 ml, 0.76 mmol) added dropwise. After 1 hour at -10° C., solids were removed by filtration and the solution added to ampicillin (anhydrous) (0.28 g, 0.8 mmol) premixed with triethylamine (0.12 ml, 0.8 mmol) in D.M.F. (10 ml) at -40° C. The solution was allowed to warm to 0° C., stirred for 90 minutes and poured into excess dry ether, with stirring. The precipitate was isolated and partitioned between ethyl acetate and water. The pH was adjusted to 7.5 (bicarbonate addition); the aqueous layer separated and acidified to pH 1.5 (HCl(5N)). Extraction with ethyl acetate, drying (Na2SO4) and evaporation gave the title product as the free penicillanic acid (0.09 g, 20%), δ((CD3)2CO) 1.50, 1.58 (2×3H, 2s, (CH3)2), 2.68 (3H, s,=C--CH3), 3.34 (3H, s, --NCH3), 4.36 (1H, s, C3 -proton), 5.53 (1H, d, J 4 Hz, C5 -proton), 5.71 (1H, d of d, J 4, 8 Hz, C6 -proton), 5.94 (1H, d, J 8 Hz, --CHCON--), 7.53 (10H, complex, aryl protons), 8.20 (1H, d, J 8 Hz, --NH--), 9.78 (1H, d, J 8 Hz, --NH--), 6.5-9 (1H, br, --CO2H). The free acid was converted to the sodium salt by addition, to an acetone solution of the free acid, of a solution of sodium ethylhexanoate (0.084 ml, 1.9N) in methyl isobutyl ketone, further addition of ether, and filtration of the precipitate. The sodium salt (2) showed vmax (nujol) 1780, 1760, 1690, 1655, 1600 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[CH:6]=[C:5]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:4]=1.S([CH2:38][N+:39]#[C-:40])(C1C=CC(C)=CC=1)(=O)=O.COCCOC>O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([NH:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH:6]=[C:7]([C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]3[O:13][CH:40]=[N:39][CH:38]=3)[CH:10]=2)[N:8]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(CCNc2cc(-c3cccc(C=O)c3)nc(OC)n2)cc1
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CCNc2cc(-c3cccc(-c4cnco4)c3)nc(OC)n2)cc1
Temperature: 85 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
In a tube is combined 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde (200 mg, 0.55 mmol), tosylmethylisocyanide (119 mg, 0.61 mmol), Ambersep 900 OH resin (1 g), ethylene glycol dimethyl ether (3.5 mL) and water (3.5 mL). The tube is sealed and the mixture is heated to 85° C. and stirred for 18 hours. The mixture is allowed to cool to ambient temperature and filtered to remove the resin, and washed the resin with 10 mL methanol. The combined filtrate and washings are concentrated by rotary evaporator and the residue is subjected to flash column chromatography on silica gel eluting with 10 to 40% EtOAc in heptane gradient, to afford [2-methoxy-6-(3-oxazol-5-yl-phenyl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [65 mg, 29.4%, Example 11(b)]. LCMS: RT=2.59 minutes MS: 403 (M+H). IC50=2.6 nM
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)Cl.[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.C(OCC)C>[C:4]([O:3][C:1]([NH:8][C@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:14]([O:16][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15])=[O:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2-dram vial containing a small stirbar was charged with Boc-tert-leucine (10a) (10 mg, 0.04 mmol), CH2Cl2 (1 mL), 4-dimethylaminopyridine (2 mg, 0.02 mmol, 0.5 equiv), benzyl alcohol (20 μL, 0.2 mmol, 5 equiv), and EDC (20 mg, 0.1 mmol, 2.5 equiv). The solution was stirred at room temperature for 3 h, and then diluted with 10 mL of diethyl ether. The mixture was washed with water (2×10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue can be further purified by flash column chromatography on silica gel (7:1 hexanes/Et2O). Both the crude and purified samples were analyzed by chiral HPLC analysis: (AD-H, 1 mL/min, 5% IPA/hexanes, 210 nm): tR(major)=9.08 min, tR(minor)=15.80 min.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)OCC1.[C:12]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:12]([C:14](=[C:5]1[CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH2:10]1)[C:15]([OH:17])=[O:16])#[N:13]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: N#CC(C(=O)O)=C1CCC(=O)CC1
Temperature: 25 °C

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-8-one (7.00 g, 44.8 mmol), tert-butyl 2-cyanoacetate (6.96 g, 49.3 mmol), ammonium acetate (0.28 g) and acetic acid (1.4 mL) in toluene (90 ml) was refluxed using Dean-Stark water separator to isolate water formed for 48 hours. The reaction mixture was washed twice with water, dried over Na2SO4, filtered, and concentrated in vacuo. To the crude material was added 140 ml of a 2% aqueous sulfuric acid solution and the mixture was refluxed for 1 hour. The reaction mixture was then cooled to room temperature and filtered to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.36-2.55 (m, 4H), 3.04 (dd, J=7.6, 5.8 Hz, 2H), 3.30 (d, J=13.6 Hz, 2H).
Reaction SMILES: C(OCC)(=O)CC(C)=O.[CH3:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][NH2:18])[CH2:13][CH2:12]1.[CH:19]1([C:22]2N(C(C)C)N=[CH:24][C:23]=2[CH:30]=[O:31])CC1>>[CH3:19][C:22]1[N:17]([CH:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)[N:18]=[CH:24][C:23]=1[CH:30]=[O:31]
Reactant: CN1CCC(NN)CC1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Solvent: CCOC(=O)CC(C)=O
Product: Cc1c(C=O)cnn1C1CCN(C)CC1

Procedure:
5-Methyl-1-(1-methyl-piperidin-4-yl)-1H-pyrazole-4-carbaldehyde was prepared from ethyl acetoacetate and (1-methyl-piperidin-4-yl)-hydrazine in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.[N+:16]([O-:19])([OH:18])=[O:17].CC1C=C(C)[N:23]([C:27](N)=[NH:28])N=1>C(O)C>[N+:16]([O-:19])([OH:18])=[O:17].[N+:16]([O-:19])([OH:18])=[O:17].[CH3:15][N:13]([CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH2:28])=[NH:23])[CH3:14]
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: CN(C)Cc1cccc(OCCCNC(=N)N)c1
Yield: 50.9 %

Procedure:
3-(3-Aminopropoxy)-N,N-dimethylbenzenemethanamine (2 g) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (2.1 g) were heated at reflux in ethanol for 16 hr. The solvent was removed and the residue was washed with boiling ethyl acetate before it was crystallised from ethanol to give the title compound as a white solid (1 g) m.p. 123°-4°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[Cl:29][CH2:30][C:31]([N:11]1[N:10]=[C:9]([CH2:8][C:7]2[C:6]([Cl:21])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12]1)=[O:32]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C(=O)CCl)N=C2Cc1c(Cl)cncc1Cl
Temperature: 25 °C
Yield: 110.5 %

Procedure:
At room temperature, under N2 and stirring, a solution of 1-[4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1H-phthalazine (1.9 g, 5.9 mmoles), prepared as described in example 22, in dry THF (70 ml) was added with triethylamine (2.05 ml, 14.7 mmoles) and cooled at 0° C. Chloroacetyl chloride (0.56 ml, 7.07 mmoles) was dropwise added and a precipitate formed. After 1 night further 50% of triethylamine and chloroacetyl chloride was added, and after 20 hours at room temperature the mixture was poured into water/ice, concentrated and extracted more times with CH2Cl2. The organic phase was washed with water, anhydrified and brought to dryness to give 2.6 g of the title compound (quantitative yield).
Reaction SMILES: C([NH:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[C:18]([S:19](=[O:25])(=[O:24])[NH:20]C(=O)C)=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:26][CH2:27][C:28]2[O:32][CH:31]=[CH:30][CH:29]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:18]([S:19](=[O:24])(=[O:25])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:26][CH2:27][C:28]2[O:32][CH:31]=[CH:30][CH:29]=2)=[CH:33][CH:34]=1
Reactant: CC(=O)Nc1ccc(Oc2c(NCc3ccco3)cc(C(=O)O)cc2S(=O)(=O)NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Oc2c(NCc3ccco3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C

Procedure:
The mixture of 1.1 g of 4-(4-acetamidophenoxy)-3-furfurylamino-5-acetylsulfamoylbenzoic acid and 11 ml of 2N aqueous sodium hydroxide is refluxed for two hours under nitrogen. After cooling to room temperature it is filtered, the filtrate acidified with glacial acetic acid to a pH of 4-5 and the precipitate formed filtered off. It is recrystallized from 70% aqueous ethanol, to yield the 4-(4-aminophenoxy)-3-furfurylamino-5-sulfamoylbenzoic acid melting at 233°-235°.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C)C=O.C(OCC)(=O)C>[CH3:24][O:23][C:21]([C:20]1[CH2:19][N:10]2[CH:9]=[CH:8][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH:1]=1)[C:11]2=3)=[O:22]
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cccc3ccn(c23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a solution of 7-formylindole (30 g, 0.206 mol) in dimethylformamide (930 mL) was added cesium carbonate (148.2 g, 0.454 mol) and the mixture was stirred vigorously at room temperature for 30 min. Methyl 3-bromopropionate (51.6 g, 0.308 mol) was added and the reaction mixture was heated to 80° C. for 24 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through a pad of Celite. The filtrate was washed with water and saturated aqueous sodium chloride, and the aqueous layers were back extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was passed through a short silica plug and concentrated under reduced pressure. Recrystallization of the crude product from chloroform and hexanes gave 4H-pyrrolo[3,2, 1-ij]quinoline-5-carboxylic acid methyl ester (17 g, 38.7% yield). Chromatography of the mother liquor gave additional 4H-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester (1.27 g, 2.9% yield) and 6H-Pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid methyl ester (0.51 g, 1.2% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].Cl.[CH3:13]O>>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=1
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1F
Agent: Cl
Product: COC(=O)c1ccc(F)c(C)c1
Yield: 83.7 %

Procedure:
To a solution of 4-fluoro-3-methylbenzoic acid (5.0 g, 32.4 mmol) in methanol (150 mL) was added concentrated hydrochloric acid (2 mL). The mixture was refluxed for 4 hrs and then concentrated. The residue was treated with ether (200 mL) and washed with water, 10% sodium hydroxide solution, water and finally brine. The organic layer was dried over sodium sulfate and solvents were removed to give 4-fluoro-3-methylbenzoic acid methyl ester (4.56 g, 83.7%) as an off-white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:3]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[OH:4].[CH3:27][O:28][B:29](OC)OC>O1CCCC1>[CH:21]1([C@H:2]2[C:3]([C:5]3[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[O:4][B:29]([O:28][CH3:27])[NH:1]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COB(OC)OC
Reactant: COc1ccc(C(O)(c2ccc(OC)cc2)[C@@H](N)C2CCCCC2)cc1
Solvent: C1CCOC1
Product: COB1N[C@@H](C2CCCCC2)C(c2ccc(OC)cc2)(c2ccc(OC)cc2)O1
Reaction time: 1.5 h

Procedure:
(S)-2-amino-2-cyclohexyl-1,1-bis-(4-methoxyphenyl)ethanol (71.1 mg, 0.2 mmol), dry tetrahydrofuran (2 mL) and trimethylborate (27.2 μL, 0.24mmol) were added to a dry flask and stirred under an atmosphere of nitrogen for 1.5 hours to form a solution of (S)-4-cyclohexyl-5,5-bis-(4-methoxyphenyl)-2-methoxy-1,3,2-oxazaborolidine. Borane dimethylsulfide complex (100 μL, 1.0 mmol) was added to this solution and the mixture was stirred at room temperature for a further 30 minutes. A solution of 3,5-(bistrifluoromethyl)-acetophenone (180 μL, 1.0 mmol) in tetrahydrofuran (3 mL) was added by means of a syringe pump at a rate of 9 mL/min and the reaction then stirred for a further 1.5 hours. Thin layer chromatography (silica gelhexane/ethyl acetate 4:1) showed no starting material. The reaction was quenched by addition of methanol. The solvent was evaporated under vacuum and the residue was dissolved in ethyl acetate and washed 3 times with 1N HCl. The ethyl acetate solution was dried over magnesium sulfate, filtered through a plug of silica gel and concentrated to give (R)-1-[3,5-(bistrifluoromethyl)phenylethanol. The enantiomer ratio was determined by HPLC using a Chiralcel OD 25 cm×4.6 mm column with hexane/2-propanol (97: 3) mobile phase at 0.7 mL/min at 25° C. Detection with UV was at 254 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:16]=[C:15]4[C:17]([C:20](O)=[O:21])=[CH:18][NH:19][C:14]4=[N:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:23][C@@H:24]([CH3:27])[CH2:25][OH:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:16]=[C:15]4[C:17]([C:20]([NH:23][C@@H:24]([CH3:27])[CH2:25][OH:26])=[O:21])=[CH:18][NH:19][C:14]4=[N:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)CO
Reactant: O=C(O)c1c[nH]c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)NC(=O)c1c[nH]c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.4 %

Procedure:
A mixture of 2-(6-chloro-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (200 mg, 0.638 mmol), (S)-2-aminopropan-1-ol (57 mg, 0.765 mmol), EDCI (366 mg, 1.914 mmol), HOBt (258 mg, 1.914 mmol) and DIPEA (247 mg, 1.914 mmol) in dry DMF (10 mL) was stirred for 16 hours at room temperature. Water (10 mL) was added, the formed precipitate was separated by filtration, washed with methanol (1 mL) then was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 30% acetonitrile/70% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 60% acetonitrile/40% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min.) to afford (S)-2-(6-chloro-1H-indazol-3-yl)-N-(1-hydroxypropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (46 mg, 26% for two steps) as a yellow solid. LCMS: (M+H)+=371; 1H NMR (300 MHz, DMSO+D2O): δ 9.14 (s, 1H), 8.59 (d, 1H, J=8.7 Hz), 8.36 (s, 1H), 7.72 (s, 1H), 7.27 (dd, 1H, J1=8.4 Hz, J2=1.8 Hz), 4.23-4.18 (m, 1H), 3.55 (d, 1H, J=4.2 Hz), 1.25 (d, 1H, J=6.6 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:21])=[O:5])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][Br:22])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Temperature: 25 °C
Yield: 105.3 %

Procedure:
A mixture of 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester (1.00 g, 3.18 mmol), N-bromosuccinimide (594 mg, 3.34 mol) and benzoyl peroxide (77 mg, 0.32 mmol) in carbon tetrachloride (15 mL) was refluxed for 16 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow oil (1.32 g, product is 80% pure by 1H NMR, impurities are starting material and dibromonated compound); MS: (+) m/z 393.9, 395.9 (M+1, 79Br/81Br).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[CH3:26]I.O>C1COCC1>[CH3:26][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:12]([CH2:11][C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([OH:2])=[O:4])[CH2:10][CH2:9]2)[C:13]1=[O:23]
Reactant: COC(=O)[C@H]1CC[C@H](Cn2c(=O)[nH]c3ccccc3c2=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)O)CC2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
trans-4-(2,4-Dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-cyclohexane carboxylic acid methyl ester (1.5 g, 4.7 mmol) was dissolved in dry THF (20 ml) under nitrogen atmosphere. NaH (0.125 g, 5.2 mmol 60% in mineral oil) was added at 0° C. The reaction mixture was allowed to reach ambient temperature and then CH3I (324 μL, 5.2 mmol) was added. The reaction mixture was left stirring at room temperature for 24 hours, few drops of water were added and the solvent was removed under reduced pressure. The residue was suspended in water and 112 mg of NaOH were added. The mixture was heated at 100° C. for 30 minutes. The solution was allowed to reach room temperature and acidified to pH 3 with HCl 6N with the formation of a white precipitate which was isolated by filtration. (1.0 g, yield 66%)
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[OH:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[NH2:54][C:55]1[CH:64]=[CH:63][C:62]2[C:57](=[C:58]([O:65][CH2:66][CH2:67][CH2:68]O)[CH:59]=[CH:60][CH:61]=2)[N:56]=1>C1COCC1>[CH3:31][C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[C:21]([O:20][CH2:68][CH2:67][CH2:66][O:65][C:58]3[CH:59]=[CH:60][CH:61]=[C:62]4[C:57]=3[N:56]=[C:55]([NH2:54])[CH:64]=[CH:63]4)[CH:22]=[CH:23][CH:24]=2)[N:29]=1
Reactant: Nc1ccc2cccc(OCCCO)c2n1
Reactant: Cc1ccc2cccc(O)c2n1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2cccc(OCCCOc3cccc4ccc(N)nc34)c2n1
Reaction time: 0.08 h

Procedure:
A 20 mL scintillation vial with a septum cap was charged with PS-PPh3 resin (Aldrich Chemical Co., Inc, 60 mg, 2.4 equiv), 8-hydroxyquinaldine (1.5 equiv) and DBAD (28 mg, 1.6 equiv) and purged by passing a stream of N2 for 45 seconds. Anhydr. THF (3 mL) was added and the contents of the vial were shaken for 5 min. Then, a solution of 3-((2-aminoquinolin-8-yl)oxy)propan-1-ol (16.7 mg/mL; 1.0 mL, 0.077 mmol) in anhydr. THF (1 mL) was added and the resulting suspension was agitated at room temperature for 8 h. Then, PS-PPh3 resin (Aldrich Chemical Co., Inc, 60 mg, 2.4 equiv) and DBAD (28 mg, 1.6 equiv) were added and the mixture was agitated at room temperature for additional 6 h. The suspension was filtered, and the resin washed with THF (3×3.0 mL). The filtrate and washings were combined and evaporated in vacuo. The residue was then treated with 6.0 mL of 4 M HCl in dioxane at room temperature for 6 h. The resulting solution was evaporated in vacuo. The residue was dissolved in 1.5 mL of a 1:1 mixture of DMSO/MeOH and purified by preparative reverse-phase HPLC. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.60 (d, 1H), 7.90 (d, 1H), 7.69 (t, 1H), 7.65 (d, 1H), 7.53 (d, 1H), 7.46 (d, 1H), 7.30 (t, 1H), 7.24 (m, 1H), 7.16 (m, 1H), 6.99 (d, 1H), 4.65 (br t, 2H), 4.48 (br t, 2H), 3.10 (s, 3H), 2.64 (m, 2H); MS (DCI/NH3) m/z 360 [M+H]+.