Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[OH:36])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46].O>CC(C)=O>[CH2:46]([O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:28]1[O:27][N:26]=[C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:12](=[O:13])[CH2:11][N:5]4[C:6]([CH:8]([F:10])[F:9])=[CH:7][C:3]([CH:2]([F:1])[F:37])=[N:4]4)[CH2:19][CH2:18]3)[S:21][CH:22]=2)[CH2:29]1)[CH:45]=[CH2:44]
Reactant: C=CCBr
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Yield: 55.1 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (81 mg) and potassium carbonate (105 mg) in acetone (5 ml) is added, at room temperature, allyl bromide (73 mg). The reaction mixture is stirred at reflux for 5 h. Then the mixture is admixed with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 1-[4-(4-{5-[2-(allyloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone (48 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:17])[CH3:16].CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+].I[C:35]1[CH:36]=[CH:37][C:38]2[O:43][CH2:42][CH2:41][CH2:40][C:39]=2[CH:44]=1>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:35]3[CH:36]=[CH:37][C:38]4[O:43][CH2:42][CH2:41][CH2:40][C:39]=4[CH:44]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Reactant: Ic1ccc2c(c1)CCCO2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)NCc1cc(-c2ccn(-c3ccc4c(c3)CCCO4)n2)ccc1Cl
Temperature: 110 °C

Procedure:
To a solution of N-[[2-chloro-5-(1H-pyrazol-3-yl)phenyl]methyl]acetamide (i.e. the product of Step B of Synthesis Example 4) (0.25 g, 1.0 mmol) in dioxane (2.5 mL) was added trans-N,N′-dimethylcyclohexane-1,2-diamine (0.065 mL, 0.40 mmol), followed by copper(I) iodide (0.076 g, 0.40 mmol), potassium carbonate (0.83 g, 6.0 mmol) and 3,4-dihydro-6-iodo-2H-1-benzopyran (0.20 g, 0.77 mmol; prepared as cited in Step E of Synthesis Example 4). The reaction mixture was heated at 110° C. for 20 h and then cooled to ambient temperature. The solvent was evaporated, and the residue was taken up in chloroform, washed with water and brine, and then dried (Na2SO4) and concentrated. The crude residue was purified by preparative TLC (2.0% methanol in dichloromethane as eluant) to provide the title product, a compound of the present invention, as a solid (0.11 g).
Reaction SMILES: Br[CH2:2][C:3]([CH2:26][CH3:27])=[CH:4][CH2:5][C:6]1[C:14]([O:15]CC[Si](C)(C)C)=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:22])=[C:8]([CH3:23])[C:7]=1[CH2:24][CH3:25].C[Si](Br)(C)C.C[O:34][P:35]([O:38]C)[O:36]C>CC#N>[CH2:26]([C:3](=[CH:4][CH2:5][C:6]1[C:14]([OH:15])=[C:13]2[C:9](=[C:8]([CH3:23])[C:7]=1[CH2:24][CH3:25])[CH2:10][O:11][C:12]2=[O:22])[CH2:2][P:35](=[O:34])([OH:38])[OH:36])[CH3:27]
Reactant: COP(OC)OC
Reactant: CCC(=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CBr
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: CCC(=CCc1c(O)c2c(c(C)c1CC)COC2=O)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A solution of 6-(3-bromomethyl-pent-2-enyl)-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (32 mg, 0.070 mmol) in trimethylphosphite (0.8 mL) was heated at 110° C. After 2 hrs the reaction was complete. The reaction was cooled to room temperature and the excess trimethylphosphite was removed in vacuo. The crude material was used in the next step without further purification. The crude product of the Arbuzov reaction was dissolved in MeCN (0.8 mL). Trimethylsilyl bromide (108.0 mg, 0.706 mmol) was added and the reaction was stirred at room temperature. After 2 hrs a second batch of trimethysilyl bromide (108.0 mg, 0.706 mmol) was added. After 3 hrs the reaction was quenched with MeOH (2 mL). The solvents were evaporated in vacuo and the crude material was purified by RP-HPLC (eluent: water/MeCN). The product-containing fractions were combined and lyophilized to yield 15.7 mg (63%) of the product. 1H NMR (300 MHz, DMSO-d6): δ=0.98-1.09 (m, 6H), 2.10 (s, 3H), 2.30 (m, 2H), 2.64 (q, J=7.5 Hz, 2H), 3.38 (m, 4H), 5.03 (m, 1H), 5.25 (s, 2H) ppm; 31P NMR (121 MHz, DMSO-d6): δ=22.26 ppm; MS=355 [M++1].
Reaction SMILES: Cl.Cl.[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(N(C(C)C)CC)(C)C.[CH:38]1([CH:43]=O)[CH2:42][CH2:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][N:26]([CH2:43][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Reactant: O=CC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(CC3CCCC3)C2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate dihydrochloride (220 mg, 0.51 mmol) in 1,2-dichloroethane (4 mL) were added diisopropylethylamine (131 mg, 1.01 mmol) and cyclopentanecarboxaldehyde (52 mg, 0.53 mmol), and the mixture was stirred at ambient temperature for 5 min. To the mixture was added sodium triacetoxyborohydride (215 mg, 1.01 mmol) and stirred for 2 hrs, and resulting mixture was poured into saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with water, and brine, and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform-MeOH=10-1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(cyclopentylmethyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (225 mg, 100%) as an amorphous powder.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[CH:8][CH:9]=[C:10]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[O:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1oc2cccc(OC)c2c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1oc2c(C(=O)c3ccccc3)ccc(OC)c2c1C

Procedure:
To a solution of ethyl 3-methyl-4-methoxybenzofuran-2-carboxylate (1.00 g, 4.27 mmol) and benzoyl chloride (1.80 g, 12.81 mmol) in 1,2-dichloroethane (12 mL) was added aluminum chloride (1.71 g, 12.81 mmol) in portions. The mixture was heated to reflux for 1.5 hours then allowed to cool and poured into 2N HCl (50 mL). The resulting mixture was extracted with methylene chloride (3×30 mL) and the combined extracts washed with saturated NaHCO3 (3×25 mL), dried (Na2SO4), and concentrated. The crude product was purified by preparative HPLC, using 25% ethyl acetate in hexane as eluant, to afford ethyl 3-methyl-4-methoxy-7-benzoylbenzofuran-2-carboxylate mp. 137°-139° C.; 1H NMR d 1.27 (2H, t, J=6 Hz), 2.67 (3H, s), 3.95 (3H, s), 4.28 (2H, q, J=6 Hz), 6.66 (1H, d, J=8 Hz), 7.44 (3H, m), 7.72 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[C:4]([C:3]1[C:2]([N:1]=[CH:12][N:13]([CH3:15])[CH3:14])=[N:9][CH:8]=[CH:7][CH:6]=1)#[N:5]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1cccnc1N
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1ncccc1C#N
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A solution of 2-Amino-nicotinonitrile (5 g, 42 mmol) and N,N-Dimethylformamide dimethyl acetal (6.13 mL, 46.2 mmol) in toluene (20 mL) was heated at reflux for 3 hours. After cooling to room temperature, the solution was concentrated under vacuum to provide the title compound (7.3 g, 100%).
Reaction SMILES: [C:1]([S:7][CH2:8]/[C:9](=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:10]([OH:12])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[O:12]=[C:10]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])/[C:9](/[CH2:8][S:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:13]\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)C(=O)SC/C(=C/c1ccccc1)C(=O)O
Reactant: CCOC(=O)CCN
Product: CCOC(=O)CCNC(=O)/C(=C\c1ccccc1)CSC(=O)C(C)(C)C

Procedure:
The (E)-2-pivaloylthiomethyl-3-phenylpropenoic acid described in Example 8 (step B) is coupled with ethyl β-alaninate according to the experimental procedure described in Example 1 (step D).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:10]([O:11][C:12](=[O:20])[NH:13]C(=O)C(Cl)(Cl)Cl)[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:21]1([CH3:29])[CH:23]([CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[O:22]1.C(N(CC)CC)C>O.C(O)C.C(OCC)C>[C:12]([O:11][CH:10]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:21]2([CH3:29])[CH:23]([CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[O:22]2)[CH:3]1[O:2][CH3:1])(=[O:20])[NH2:13]
Reactant: COC1C(OC(=O)NC(=O)C(Cl)(Cl)Cl)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC1C(OC(N)=O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
A solution of 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-6-(trichloroacetylcarbamoyloxy)-1-oxaspiro[2,5]octane (26 mg) and triethylamine (9.9 μl) in a mixture of water (0.8 ml) and ethanol (0.8 ml) was stirred overnight at ambient temperature. The mixture was diluted with diethyl ether and washed with brine. The mixture was dried and evaporated to yield 6-carbamoyloxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (18.2 mg) as white solids.
Reaction SMILES: NC1C=C(C(F)(F)F)C=C(F)[C:3]=1[OH:13].[N+:14]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1Cl)([O-:16])=[O:15].C[O-].[Na+]>>[N+:14]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:13][CH3:3])([O-:16])=[O:15]
Reactant: Nc1cc(C(F)(F)F)cc(F)c1O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The 2-amino-4-trifluoromethylphenols (XI) required for the reaction sequence just described may be prepared by conventional methods. Thus, 2-amino-6-fluoro-4-trifluoromethylphenol may be prepared from 2-nitro-4-trifluoromethylchlorobenzene by reacting the latter with sodium methoxide to give 2-nitro-4-trifluoromethylanisole, and reducing this compound to 2-amino-4-trifluoromethylanisole. The latter compound may be diazotised and converted to its fluoborate salt and heated to give 2-fluoro-4-trifluoromethylanisole. This may then be nitrated to form 2-fluoro-6-nitro-4-trifluoromethylanisole, which is then reduced to give 2-amino-6-fluoro-4-trifluoromethylanisole. Finally the latter compound is heated with a demethylating agent, for example an excess of pyridine hydrochloride to give 2-amino-6-fluoro-4-trifluoromethylphenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:14]=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.ClC1C=CC(C(=CO)C(OCC)=O)=CC=1.C([O-])=O.[NH4+:34]>CCO>[NH2:34][CH:14]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: [NH4+]
Reactant: CCOC(=O)C(C=O)c1ccc(Cl)cc1
Agent: CCOC(=O)C(=CO)c1ccc(Cl)cc1
Agent: O=C[O-]
Solvent: CCO
Product: CCOC(=O)C(=CN)c1ccc(Cl)cc1
Temperature: 65 °C
Yield: 84.6 %

Procedure:
A ˜1:1 mixture of ethyl 2-(4-chlorophenyl)-3-oxopropanoate/ethyl 2-(4-chlorophenyl)-3-hydroxyacrylate (50.0 g, 0.22 mol, 1.0 equiv) and ammonium formate (69.6 g, 1.10 mol, 5.0 equiv) in EtOH (500 mL, 10 vol) was heated at 65° C. for 8 h. Reaction was monitored by HPLC (IPC by LCMS (m/z): [M]+ shows 225.9). The reaction mixture was then concentrated under reduced pressure to a minimal working volume. The mixture was partitioned between cold water (200 mL) and EtOAc (200 mL). The organic phase was separated and washed with saturated aqueous NaHCO3 (100 mL) and brine (3×100 mL). The organics were dried over anhydrous Na2SO4, filtered and concentrated to give crude product ethyl 3-amino-2-(4-chlorophenyl)acrylate (42 g, 85% yield) as an unassigned mixture of E/Z isomers (˜1:1) and brown oil. The crude product was used directly for next step without further purification.
Reaction SMILES: [C:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)=[CH:8][CH:7]=1)(O)=[O:2].S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][C:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)=[CH:8][CH:7]=1)=[O:2]
Reactant: O=C(O)C=Cc1ccc(OC(=O)c2ccc(F)c(F)c2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C=Cc1ccc(OC(=O)c2ccc(F)c(F)c2)cc1
Temperature: 35 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
About 10 g (about 21.68 mmol) of 3,4-difluoro-benzoic acid 4-(2-carboxy-vinyl)-phenyl ester was dissolved in about 200 ml of methylene chloride, and about 2.84 g (23.848 mmol) of thionyl chloride (SOCl2) was added thereto. Thereafter, the reaction mixture was stirred at about 35° C. for about 6 hours, followed by removing the solvent. Subsequently, a vacuum drying process was conducted, thus obtaining the desired compound (Yield about 90%).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI.CCOCC>CN(C=O)C>[CH3:12][N:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]1=[O:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1cnc(O)c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOCC
Product: Cc1cc([N+](=O)[O-])c(=O)n(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a suspension of 10 g (63.6 mmol) 2-hydroxy-5-methyl-3-nitropyridine and 17.58 g (127 mmol) K2CO3 in 100 ml DMF, 5.96 ml (95 mmol) MeI was added at 0° C. Afterwards the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, diluted with water and extracted three times with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered and concentrated to obtain an orange slurry. The residue was treated with ether and the precipitate was filtered off and dried under high vacuum to obtain 9.74 g (57.9 mmol, 91% yield) of the title compound as an orange solid. LCMS: (M+H)=169; tR=0.47 min (LC-MS 6). HPLC: tR=1.70 min (HPLC 8). 1H-NMR (DMSO-d6, 400 MHz) δ ppm 8.30 (d, 1H) 8.08 (m, 1H) 3.50 (s, 3H) 2.09 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C1COCCN1
Reactant: O=Cc1sccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Brc1ccsc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of 3-bromothiophene-2-carbaldehyde (500 mg, 2.62 mmol) and morpholine (0.68 mL, 7.85 mmol) and CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.11 g, 5.24 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (100 mL) and the organic layer was washed with brine then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH in CH2Cl2) to afford the sub-title compound (580 mg, 84%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)=[O:9])[C:4](=[O:26])[N:3]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Br[C:34]1[C:35]([NH2:41])=[N:36][CH:37]=[C:38]([Br:40])[N:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:41][C:35]1[C:34]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:26])[N:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[CH:16][CH:15]=2)=[N:39][C:38]([Br:40])=[CH:37][N:36]=1
Reactant: Cc1c(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ncc(Br)nc1Br
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)Nc2ccc(-c3nc(Br)cnc3N)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
A suspension of the compound prepared in Example 2 (15 g), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (2.0 g), 3,5-dibromopyrazin-2-amine (9.5 g), and sodium carbonate (Na2CO3) (7.3 g) in 3:1 mixture of dioxane/water (350 mL) was degassed with a stream of nitrogen for 10 minutes. The reaction was heated at 90° C. for 5 hours, at which time LC/MS indicated the reaction was complete. The mixture was concentrated under reduced pressure, diluted with water (200 mL) and extracted with EtOAc (3×300 mL). The organic layers were combined, dried over Na2SO4, and evaporated under reduced pressure. The product was absorbed onto silica gel (40 g) and purified by flash chromatography (silica gel, 400 g) using a gradient of 1 to 3% MeOH in DCM as the eluent. After purification, 1H NMR showed that pinicol was present as an impurity. The product was suspended in 10% aqueous potassium carbonate (300 mL), stirred for 30 minutes, filtered and washed with water (3×100 mL). The resulting solid was then evaporated from absolute ethanol (6×50 mL) to give the title compound (6.6 g) having the following physical data as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[CH2:20]1[N:25]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:24][CH2:23][O:22][CH2:21]1.C(N(C1C=CN=CC=1)C1C2C(=NC=CN=2)N=C(C2C=C(Br)C=CC=2F)N=1)CCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[N:17]=[C:16]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([N:25]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[CH:31][CH:30]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CCCCN(c1ccncc1)c1nc(-c2cc(Br)ccc2F)nc2nccnc12
Product: Fc1ccc(Br)cc1-c1nc(Nc2ccc(N3CCOCC3)cc2)c2nccnc2n1

Procedure:
The title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(4-morpholino)aniline following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[O:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[Cl:22][C:23]1[O:27][C:26]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[CH:25][CH:24]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(Cl)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Cl)o4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 2.7 %

Procedure:
To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (5-chloro-2-furyl)methanol (94 mg), tributylphosphine (0.264 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (3.8 mg) as an off-white solid.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:28])[C:5]([C:3]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(-c3cccs3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3cccs3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-thiophen-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.077 mmol), β-alanine (886 mg, 9.9 mmol) and NaOMe solution (15 mL, 7.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH 1 with 1 M HCl, and the resulting precipitate was isolated by filtration to give 20 mg of the title compound as a brown solid. MS: (+) m/z 450.24 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:15][OH:16])[CH2:10][CH2:11][CH2:12][C:13]#[N:14])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl[CH2:19][CH2:20][NH2:21].[OH-].[K+].CN(C)C=O>Cl>[ClH:1].[NH2:21][CH2:20][CH2:19][O:16][N:15]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][C:13]#[N:14]
Reactant: NCCCl
Reactant: N#CCCCC(=NO)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#CCCCC(=NOCCN)c1ccc(Cl)c(Cl)c1

Procedure:
5.0 mmol (1.29 g) of 3', 4'-dichloro-4-cyanobutyrophenone oxime (melting point 122°-123° C), 5.2 mmol (0.60 g) of 2-chloroethylamine hydrochloride and 0.7 g of powdered potassium hydroxide were added, in this sequence and while stirring at 10° C, to 12 ml of dimethylformamide (D.M.F). After stirring for 2 days at room temperature the D.M.F. was evaporated invacuo, the residue was brought in water and 2N hydrochloric acid was then added while stirring until pH 3. The remaining oxime was removed by means of ether. The acid aqueous solution was then rendered alkaline with 15 ml of 2N sodium hydroxide solution and then extracted three times with ether. After washing with a 5% sodium bicarbonate solution, drying over sodium sulphate and evaporating the ether, the free base was obtained. This was dissolved in alcoholic hydrochloric acid. After evaporating the ethonal, the above entitled compound was crystallized from isopropanol/ether (1 : 1). Melting point 129°-130° C.