Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:17]=[CH:16]C(F)=[CH:14][C:13]=1O[C@H](CC=C)C>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C@H:17]([CH2:12][CH:13]=[CH2:14])[CH3:16]
Reactant: Cc1cc(O)c(Br)cc1F
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1Br
Product: C=CC[C@H](C)Oc1cc(C)c(F)cc1Br
Yield: 59 %

Procedure:
Prepared in 59% yield from 2-bromo-4-fluoro-5-methylphenol following the same procedure as (S)-1-bromo-4-fluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J=8.8 Hz, 1H), 6.75 (d, J=6.8 Hz, 1H), 5.91 (ddt, J=17.2, 10.2, 7.2 Hz, 1H), 5.20-5.07 (m, 2H), 4.42-4.26 (m, 1H), 2.60-2.48 (m, 1H), 2.45-2.37 (m, 1H), 2.23 (d, J=1.8 Hz, 3H), 1.33 (d, J=6.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[NH:6][C:7]=1[NH2:8].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>O.C(O)(=O)C>[NH2:8][C:7]1[NH:6][C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[C:2]=1[NH:1][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=1
Reactant: Cn1c(=O)[nH]c(N)c(N)c1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)[nH]c(N)c(NCc2ccc(Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.7 %

Procedure:
To a solution of 5,6-diamino-3-methylpyrimidine-2,4(1H,3H)-dione (0.8 g, 5.13 mmol) in water (10 mL) and acetic acid (0.5 mL) was added 4-chlorobenzaldehyde (0.72 g, 5.14 mmol), the mixture was stirred at room temperature for 5 h. The mixture was cooled to 0° C., sodium cyanoborohydride (0.3 g, 4.76 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated and filtered, and the filter cake was washed with methanol, dried in vacuo to give 6-amino-5-(4-chlorobenzylamino)-3-methylpyrimidine-2,4(1H,3H)-dione (0.6 g, 42.9% yield) as yellow solid. LCMS MH+ 281.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li].[CH:7]([C@@H:9]1[N:13]([CH3:14])[C:12](=[O:15])[CH2:11][C@@H:10]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:8].[NH4+].[Cl-]>C1COCC1>[OH:8][C@H:7]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C@@H:9]1[N:13]([CH3:14])[C:12](=[O:15])[CH2:11][C@@H:10]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Reactant: c1ccsc1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1cccs1
Temperature: 0 °C
Yield: 26.7 %

Procedure:
To a −50° C. solution of lithium thiophene (1M in THF, 170 mL, 170 mmol) was added a solution of (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 127 mmol) in THF (10 mL). The reaction mixture was allowed to warm to 0° C. over 45 min and treated with a saturated NH4Cl solution. The resulting mixture was extracted with EtOAc, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (67% EtOAc/hex) to give (±)-(4R*,5R*)-5-((1S*)-hydroxy-2-thienylmethyl)-1-methyl-4-phenylpyrrolidin-2-one (9.76 g, 27%): TLC (EtOAc) Rf 0.42.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>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.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: C#CC(O)CC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (28.5 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 3 supra) using (Ph3P)2PdCl2 (9.5 mg) and Cul (2.6 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give rac-(Z)-1,3-dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 17 mg, 39%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8])#[N:2].N.[H][H]>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: [H][H]
Reactant: CCOC(OCC)P(=O)(CCC#N)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CCCN)OCC

Procedure:
A solution of 9.6 g of ethyl 2-cyanoethyl(diethoxymethyl)phosphinate in 450 ml of ethanol is added to 82 g of an 8% solution of ammonia in ethanol. To this is added 5 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered, the filtrate is concentrated under reduced pressure and the crude product is distilled to give ethyl 3-aminopropyl(diethoxymethyl)phosphinate, b.p. 150° C./0.01 mbar, 31 p=+46.4 ppm (CDCl3).
Reaction SMILES: S(Cl)(C)(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH:16]([CH2:18]O)[CH:15]([OH:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(Cl)Cl.[N-:24]=[N+:25]=[N-:26].[Na+]>N1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH:15]([OH:20])[CH:16]([CH2:18][N:24]=[N+:25]=[N-:26])[CH2:17]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC(O)C(CO)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(O)C(CN=[N+]=[N-])C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Ms-Cl (0.38 mL, 2.6 eq) was added to a solution of 3-hydroxy-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (mixture of stereoisomers, prepared according to WO9303026, 410 mg, 1.89 mmol) in pyridine (3.5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. Then DCM was added and the mixture was washed with sat. aq. NaHCO3, dried over MgSO4, concentrated under reduced pressure and dried at HV. The crude mesylate was dissolved in DMF (18 mL), treated with NaN3 (1.23 g, 10 eq) and stirred at 95° C. for 1.5 h. After cooling to rt the mixture was concentrated to dryness and dissolved in DCM. The org. layer was washed with water, dried over MgSO4, concentrated under reduced pressure and the residue was purified by CC (DCM to DCM/MeOH 95:5) to afford the title intermediate as a yellow oil (390 mg, 85%).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.C(Cl)(Cl)Cl>[N:9]1([C:2]2[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH:13]=[CH:12][CH:11]=[N:10]1
Reactant: c1cn[nH]c1
Reactant: Nc1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: Nc1ccc(-n2cccn2)nc1
Temperature: 120 °C
Yield: 16.8 %

Procedure:
Commercial 6-fluoropyridin-3-amine (500 mg, 4.46 mmol) was dissolved in 20 mL dry NMP. To it were added pyrazole (910 mg, 13.4 mmol) and cesium carbonate (4.4 g, 13.4 mmol). The mixture was stirred in a sealed tube at 120° C. for over the weekend (3 nights). The mixture was diluted with chloroform, washed with brine (3 times), dried, concentrated and subjected to flash column (0 to 30% EtOAc in DCM) to isolate 6-(1H-pyrazol-1-yl)pyridin-3-amine (120 mg, 17% yield).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8][C:7]2=O.[OH-].[Na+].O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][C:2]([F:16])([F:15])[F:1])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc[nH]c2ccc(OC(F)(F)F)cc12
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)Oc1ccc2nccc(Cl)c2c1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
In a 25 mL round bottom flask was dissolved 6-(trifluoromethoxy)quinolin-4(1H)-one (0.50 g, 2.18 mmol) in POCl3(3.05 mL). A reflux condenser was attached and the reaction mixture was stirred at 130° C. for 3 hours. The reaction turned dark brown and became homogeneous. The reaction was cooled to RT, poured slowly into ice bath while stirring. A thick gum resulted, which was basified with 6N NaOH to give a dark brown solution. The solution was extracted into ethyl acetate, washed 1× water, 1× NaCl, dried with Na2SO4, filtered through fritted funnel, concentrated down. The curde material was purified using an Isco silica gel chromatography system eluting with a solvent gradient of 0-100% CH2Cl2:MeOH(90:10)/CH2Cl2. The product fractions were concentrated down to yield 4-chloro-6-(trifluoromethoxy)quinoline as an orange oil. MS [M+H]=248.0; Calc'd 247.6 for C10H5ClF3NO.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][C:13]1[CH:26]=[CH:25][C:16]2[C:17]([C:21]([NH:23][CH3:24])=[O:22])=[C:18]([CH3:20])[S:19][C:15]=2[CH:14]=1.Br[CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH3:24][NH:23][C:21]([C:17]1[C:16]2[CH:25]=[CH:26][C:13]([O:12][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:28][CH2:29][CH:30]5[CH2:34][CH2:33][CH2:32][N:31]5[CH3:35])[CH:3]=4)[N:8]=[CH:7][CH:6]=3)=[CH:14][C:15]=2[S:19][C:18]=1[CH3:20])=[O:22]
Reactant: CNC(=O)c1c(C)sc2cc(Oc3ccnc4ccc(O)cc34)ccc12
Reactant: CN1CCCC1CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CNC(=O)c1c(C)sc2cc(Oc3ccnc4ccc(OCCC5CCCN5C)cc34)ccc12

Procedure:
A solution of 25-F (70 mg, 0.19 mmol), 2-(2-bromoethyl)-1-methylpyrrolidine 25-B (110 mg crude and Cs2CO3 (94 mg, 1.5 mmol) in DMSO (2 ml) was heated to 120° C. for 2 hours. The title compound, N,2-dimethyl-6-({6-[2-(1-methylpyrrolidin-2-yl)ethoxy]quinolin-4-yl}oxy)-1-benzothiophene-3-carboxamide 25 (21 mg) was isolated by HPLC (Dionex System) using 20-60% CH3CN/H2O (0.1% AcOH) over 30 minutes.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:45]([S:52][CH:53]([CH:56]([O:59][CH3:60])[O:57][CH3:58])[CH2:54][NH2:55])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C=O.O>[CH2:45]([S:52][CH:53]([CH:56]([O:57][CH3:58])[O:59][CH3:60])[CH2:54][NH:55][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[N:2]([CH3:1])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:17])=[O:13])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(OC)C(CN)SCc1ccccc1
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)C(CNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.4 %

Procedure:
To a solution of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.662 g) in N,N-dimethylformamide (20 ml) were added 1H-1,2,3-benzotriazol-1-ol (0.414 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.292 g) and 2-(benzylthio)-3,3-dimethoxypropan-1-amine (0.500 g), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-60:40) to give the title compound (0.776 g, yield 70%) as a colorless amorphous solid.
Reaction SMILES: [ClH:1].[CH3:2][C@H:3]1[N:8]([C:9]2[C:10]3[CH:17]=[CH:16][S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C@@H:7]([CH3:18])[CH2:6][N:5]([CH2:19][C:20](O)=[O:21])[CH2:4]1.C(Cl)(=O)C([Cl:26])=O>ClCCl.CN(C)C=O>[ClH:26].[CH3:2][C@H:3]1[N:8]([C:9]2[C:10]3[CH:17]=[CH:16][S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[C@@H:7]([CH3:18])[CH2:6][N:5]([CH2:19][C:20]([Cl:1])=[O:21])[CH2:4]1
Reactant: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2sccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H]1CN(CC(=O)Cl)C[C@H](C)N1c1ncnc2sccc12

Procedure:
A mixture of the product from Example 9 step (ii) (1.15 g) and oxalyl chloride (1.2 ml) in dichloromethane (100 ml) was treated with 2 drops of dimethylformamide. After 24 hours at room temperature a further aliquot of oxalyl chloride (3.6 ml) was added and the mixture heated under reflux for 48 hours. The solvent was evaporated under reduced pressure. Toluene was added to the residue and then evaporated under reduced pressure to give the subtitle product as a yellow oil (0.95 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1>>[N+:22]([C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:21]=[CH:20][CH:19]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccc([N+](=O)[O-])c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (102 mg, 0.54 mmol) and 1-iodo-3-nitrobenzene (146 mg, 0.58 mmol) according to the general procedure IC to give 113 mg (67%) of a pale orange solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.30 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 8.36-8.35 (m, 1H), 8.18-8.14 (m, 1H), 7.82-7.79 (m, 1H), 7.55-7.46 (m, 3H), 7.23-7.20 (m, 2H), 3.68 (s, 3H), 3.01-2.96 (t, 2H, J=7.8 Hz), 2.68-2.62 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3): δ 173.0, 148.2, 141.8, 137.1, 131.9, 129.3, 128.5, 126.3, 125.2, 122.8, 120.1, 91.9, 86.6, 51.7, 35.3, 30.8; EI-MS m/z 309 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23])([O-])=O>CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:20][CH2:21][C:22]([F:23])([F:24])[F:25]
Reactant: CCOC(=O)C1(c2ccc([N+](=O)[O-])c(OCC(F)(F)F)c2)CCCC1
Solvent: CO
Product: CCOC(=O)C1(c2ccc(N)c(OCC(F)(F)F)c2)CCCC1
Reaction time: 6 h
Yield: 81.8 %

Procedure:
To a stirred solution of ethyl 1-(4-nitro-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentane carboxylate (10 g), in dry MeOH (100 mL) Pd(OH)2 (2 g) was added and reduced under an atmosphere of H2 for 6 h at room temperature. The mixture was filtered through a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (7.5 g) as a thick liquid.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:12]=[N:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21].N12CCN(CC1)CC2.O>CN(C)C=O>[CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC1CCCCC1)Nc1ccc(O)nc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Oc1ccc(NC(=O)CC2CCCCC2)cn1)c1ccccc1
Yield: 71.7 %

Procedure:
A solution of 2-cyclohexyl-N-(6-hydroxy-pyridin-3-yl)-acetamide (0.70 g, 3.00 mmol), N -methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.79 g, 72% yield) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2].[Cl:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:26][CH2:25][O:24][CH2:23][CH2:22][Cl:21])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: ClCCOCCCl
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCCl
Reaction time: 24 h
Yield: 72 %

Procedure:
A mixture of 6.0 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 25 ml of bis(2-chloroethyl)ether and 2.2 g of anhydrous potassium carbonate in 150 ml of anhydrous acetone was stirred at reflux. After 24 hours, 2 g of potassium iodide and 50 ml of anhydrous dimethylformamide were added and reflux was continued. After 50 hours, 2.2 g of potassium carbonate and 2 g of potassium iodide were added and after 77 hours, 2.0 g of potassium carbonate was added. After a total reflux time of 108 hours, the reaction mixture was concentrated in vacuo and the residue was purified by high pressure liquid chromatography using 25% ethyl acetate-hexane to give 5.96 g (72% yield) of [4-acetyl-3-[2-(2-chloroethoxy)ethoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]1[CH2:25][CH2:24][CH:23]=[CH:22]1.N(OC(C)(C)C)=O>O1CCCC1>[C:19]([C:4]1[C:3]([CH:21]2[CH2:25][CH2:24][CH:23]=[CH:22]2)=[CH:2][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1C=CCC1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1C=CCC1
Temperature: 67.5 °C
Yield: 59.3 %

Procedure:
To 5-amino-3-cyano-4-(cyclopent-2-enyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (300 mg, 0.77 mmol, Example 7) in dry tetrahydrofuran (THF) (8 ml ) heated at 65° C. was added dropwise tert-butyl nitrite (239 mg, 2.3 mmol) in dry THF (2 ml) over 30 min. The solution was heated for a further 3 hr at 65-70° C. The solvent was removed in vacuo and the resulting brown oil was purified by silica chromatography (eluting with DCM) to yield 170 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]=1[NH2:8].[CH:15](S([O-])(=O)=O)(O)[CH:16](S([O-])(=O)=O)O.O.[Na+].[Na+]>Cl>[CH2:9]([N:6]1[C:7]2[C:2](=[N:1][CH:15]=[CH:16][N:8]=2)[C:3](=[O:14])[NH:4][C:5]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: O=S(=O)([O-])C(O)C(O)S(=O)(=O)[O-]
Reactant: CC(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)Cn1c(=O)[nH]c(=O)c2nccnc21
Yield: 19.3 %

Procedure:
After dissolving 19.8 g (100 mmol) 5,6-diamino-1-isobutyluracil in 1 liter of 1N HCl at 70° C., 186.3 g of glyoxal sodium bisulfite addition compound hydrate was added and the mixture refluxed for 1 hour. After extracting the mixture several times with ethyl acetate, the collected ethyl acetate fractions were washed with water, dried over MgSO4 and evaporated. The crude product was purified by preparative column chromatography using chloroform/methanol 9:1 as eluant yielding 4.25 g (18%) of 1-isobutyl-1H-pteridine-2,4-dione (m.p. 200–201° C., Lit. 195–197° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:32])[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH3:23])[CH:17]=2)=O)=[CH:8][CH:7]=1.Cl.[NH2:34][OH:35].C([O-])(O)=O.[Na+]>>[OH:1][CH2:2][CH2:3][N:4]([CH3:32])[C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:13]/[C:14](=[N:34]\[OH:35])/[C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH3:23])[CH:17]=2)=[CH:8][CH:7]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N(C)CCO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N(C)CCO)cc1

Procedure:
In analogy to example 151, step 3, N-(2-hydroxy-ethyl)-N-methyl-4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=448.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@@H:7]([CH3:18])[CH2:6][NH:5]2.N1C=CC=CC=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:28]([CH:25]1[CH2:27][CH2:26]1)=[O:29]
Reactant: O=C(Cl)C1CC1
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)C2CC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
A 250-mL, three-necked, round bottomed flask fitted with a nitrogen inlet, magnetic stir bar, and thermocouple was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-2,2,2-trifluoroethanone (7.0 g, 21.66 mmol), dichloromethane (140 mL), and pyridine (2.63 mL, 32.5 mmol). The mixture was cooled to 0° C. and cyclopropanecarbonyl chloride (2.36 mL, 26.0 mmol) was slowly added while maintaining the internal temperature below 7° C. The reaction mixture was stirred cold for 30 min. and then warmed to rt. The reaction mixture was washed with 1 M aqueous HCl solution (25 mL) and water (25 mL), and the combined organic layers were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 4:1 hexanes-ethyl acetate) to afford (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (8.26 g, 97%) as an off-white solid. MS (ESI, pos. ion) m/z 392 [M+1]+.
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH:25]=[CH:24]2>CO>[OH:1][C@@H:2]([CH2:18][N:34]1[CH2:33][CH2:32][CH:31]([C:26]2[CH:25]=[CH:24][C:23]3[C:28](=[CH:29][CH:30]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH:27]=2)[CH2:36][CH2:35]1)[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10]
Reactant: O=C1OCCC1=Cc1ccccc1OC[C@@H]1CO1
Reactant: COc1ccc2cc(C3CCNCC3)ccc2c1
Solvent: CO
Product: COc1ccc2cc(C3CCN(C[C@H](O)COc4ccccc4C=C4CCOC4=O)CC3)ccc2c1
Yield: 42.1 %

Procedure:
(S)-α-(2′-(2,3-Epoxypropan-1-yloxy)benzylidene)-γ-butyrolactone (1.2 g) and 4-(6-methoxynaphthalen-2-yl)piperidine (1.2 g) were dissolved in methanol (50 ml), and the mixture was refluxed under heating for 2 hr. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.0 g), melting point 148–150° C.