Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:25])[CH2:9][CH2:10][NH:11][C:12]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:13]=1[C:14](OCC)=[O:15]>O1CCCC1>[CH3:7][N:8]([CH3:25])[CH2:9][CH2:10][NH:11][C:12]1[C:13]([CH2:14][OH:15])=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[N:22]=1
Reactant: CCOC(=O)c1c(C)cc(C)nc1NCCN(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(CO)c(NCCN(C)C)n1

Procedure:
To a suspension of lithium aluminum hydride (3.5 g, 92 mmol) in dry tetrahydrofuran (160 ml) is added dropwise a solution of crude ethyl 2-(2-dimethylaminoethylamino)-4,6-dimethylnicotinate (18.5 g, 70 mmol) in dry tetrahydrofuran (100 ml) under a nitrogen atmosphere. Reaction mixture is refluxed for 11/2 hours, cooled, quenched with saturated sodium sulfate solution filtered, dried and evaporated to give 15.0 g of crude title C product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][NH:10]2)=[CH:6][CH:5]=1.I[CH3:18]>C1COCC1>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][N:10]2[CH3:18])=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=C(O)Cc1c[nH]c2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CC(=O)O)c2ccc(Cl)cc21
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.19 g of 60% suspension in oil) was suspended in dry THF (10 ml). 6-Chloroindole-3-acetic acid (SR058)(100 mg, 0.48 mmol) in THF (5 ml) was added dropwise and the mixture then stirred for 10 minutes. Iodomethane (0.34 g, 2.4 mmol) was then added, and the mixture stirred overnight. Excess sodium hydride was carefully destroyed by dropwise addition of water, and then the mixture was acidified (1M HCl) and extracted with ethyl acetate (3×50 ml), the organic layers dried over MgSO4, and the solvent evaporated to give a brown powder, yield 75 mg, 70%, m.p. 130-132° C. dec.; m/z 225, 223 (M+), 180, 178 (M+-CO2H); δH/ppm 7.46-6.92 (4H, m, Ar—H), 3.77 (3H, s, N—Me), 3.70 (2H, s, ArCH2).
Reaction SMILES: [CH2:1]1CCN2C(=NCCC2)CC1.[C:12]1([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.O>[C:12]1([CH:18]([CH3:22])[C:19]([O:21][CH3:1])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C(=O)O)c1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C)c1ccccc1
Temperature: 90 °C

Procedure:
DBU (2.03 g, 13.3 mmol) was added to a mixture of 2-phenylpropionic acid (2.0 g, 13.3 mmol) in DMC (20 mL) and the resulting mixture was heated to reflux (90° C.) for 5 hours. The reaction mixture was cooled to ambient temperature and diluted with CH2Cl2 (50 mL) and water (40 mL). The organic layer was separated and washed in sequence with 2 M HCl (2×40 mL), saturated aqueous NaHCO3 (40 mL) and water (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give methyl 2-phenylpropionate as an oil.
Reaction SMILES: Cl[Sn]Cl.[N+:4]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1)([O-])=O.Cl>C1COCC1>[C:15]1([C:14]#[C:13][C:11]2[CH:12]=[C:7]([CH:8]=[C:9]([C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:10]=2)[NH2:4])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cc(C#Cc2ccccc2)cc(C#Cc2ccccc2)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: Nc1cc(C#Cc2ccccc2)cc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
A solution of SnCl2 (0.96 g, 5.10 mmol) was added slowly (1 h) to the mixture of ((5-nitro-1,3-phenylene)bis(ethyne-2,1-diyl))dibenzene (0.33 g, 1.02 mmol) and HCl (1 mL) in THF (10 mL). The reaction mixture was stirred at room temperature for 3 hours. After neutralization with NaOH (1.0 N solution), the product was extracted with EtOAc and dried over (Na2SO4). Solvent was evaporated to afford 0.26 g (86%) of the product: 1H-NMR (400 MHz, CDCl3) δ 7.51 (m, 4H), 7.34 (m, 6H), 7.14 (t, J=1.3 Hz, 1H), 6.82 (d, J=1.3 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[CH:32][CH:31]=[CH:30]3)O1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[N:33]=[CH:32][CH:31]=[CH:30]4)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CC1(C)OB(c2ccc3ncccc3c2)OC1(C)C
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc4ncccc4c3)cccc2c1N
Yield: 89 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolane-2-yl)quinoline (247 mg, 0.97 mmol) were reacted to afford the title compound (105 mg, 91.9% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.96 (dd, J=4.2 Hz, J′=1.7 Hz, 1H), 8.56 (br, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.05-8.15 (m, 2H), 7.88-7.96 (m, 2H), 7.78 (t, J=7.7 Hz, 1H), 7.44 (dd, J=8.2 Hz, J′=4.2 Hz, 1H), 3.47 (q, J=6.7 Hz, 2H), 1.67 (m, J=7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H) MS APCI, m/z=358 (M+H) HPLC 1.47 min.
Reaction SMILES: CI.[CH3:3][O:4][CH:5]([O:10][CH3:11])[CH2:6][C:7](=O)[CH3:8].C[CH2:13][O:14]CC>>[CH3:3][O:4][CH:5]([O:10][CH3:11])[CH2:6][CH:7]([CH2:13][OH:14])[CH3:8]
Reactant: COC(CC(C)=O)OC
Reactant: CCOCC
Solvent: CI
Product: COC(CC(C)CO)OC
Temperature: 25 °C
Yield: 54 %

Procedure:
CH3I (18.5 mL, 297 mmol) in 50 mL of ether was added slowly, to maintain reflux, to a suspension of Mg (6.0 g, 250 mmol) in 50 mL of ether. The solution was vigorously stirred during the addition. After the magnesium was consumed, the solution was chilled with an ice bath to ≅5° C. Acetylacetaldehyde dimethyl acetal (16.5 mL, 124 mmol) in 50 mL of ether was added very slowly, over a period of 2 h. After the addition was complete, the reaction was stirred for an additional hour while warming to room temperature. The reaction was quenched with 1 mL of saturated (NH4)2SO4 (aq) and filtered. The residue was washed with ether (2×50 mL). The combined filtrates were dried over Na2SO4, and the solvent was removed under water aspirator vacuum (67 mmol, 54% yield). Distillation of the residue yielded 9.9 g of 3-hydroxymethylbutanal dimethyl acetal, bp4.2 53°-56° C. bp10 60°-65° C., bp14 72°-79° C. in agreement with Malik, O. P.; Kapil, R. S., Anand, N., Ind. J. Chem. 14B (1976) 449); 1H--NMR (200 MHz, CDCl3) δ 1.24 (s, 6H, CH3), 1.80 (d, J=5.9 Hz, 2 H, CH2), 3.36 (s, 6 H, CH3O), 3.41 (s, 1 H, OH), 4.66 (t, J=5.9 Hz, 1 H, CH), 13C--NMR (50 MHz, CDCl3) δ 29.46 (CH3), 43.85 (CH2), 52.61 (CH3O), 68.63 (COH), 102.51 (CH).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([O:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:33]([C:31]1[N:32]=[C:20]2[N:19]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:17][CH:16]=3)[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][N:21]2[N:30]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(Oc5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(-c3nc4nc(Oc5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 6-8 (24 mg, 0.04 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 6-9.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][C:12]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=1)=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.[Sn:29](Cl)([CH3:32])([CH3:31])[CH3:30]>C(OCC)C.C1COCC1>[CH3:23][C:18]1[CH:17]=[C:16]([C:12]2[CH:13]=[CH:14][C:15]3[C:10]([CH:11]=2)=[N:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2]=3[Sn:29]([CH3:32])([CH3:31])[CH3:30])[CH:21]=[C:20]([CH3:22])[CH:19]=1
Reactant: Cc1cc(C)cc(-c2ccc3c(Br)c4ccccc4nc3c2)c1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2ccc3c([Sn](C)(C)C)c4ccccc4nc3c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of 9-bromo-3-(3,5-dimethylphenyl)acridine, 29, (0.6 g, 1.6 mmol) in 10 ml anhydrous diethyl ether:THF (1:1) was cooled to −78° C. To the solution was added 1.6 M n-BuLi in hexanes (2.4 mmol, 1.5 mL) dropwise over a period of 15 min and then a 1.0 M solution of Me3SnCl in hexanes (3 mL, 3 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 18 hours and concentrated in vacuo. Purification of the orange residue by flash chromatography (100:30:1 hexanes:ethyl acetate:triethylamine) afforded 30 (0.65 g, 91%) as a yellow solid. GC-MS revealed contamination of the product with 5-10% 3-(3,5-dimethylphenyl)acridine that could not be separated by chromatography. The stannane was therefore employed in the Stille cross-coupling with 1,8-dibromonaphthalene without filter purification. 1H-NMR δ=0.70 (s, 9H), 2.44 (s, 6H), 7.08-7.10 (m, 1H), 7.49-7.56 (m, 3H), 7.76 (ddd, J=1.4 Hz, 6.6 Hz, 8.8 Hz, 1H), 7.88 (dd, J=1.9 Hz, 9.1 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 8.22 (d, J=9.1 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H), 8.49 (m, 1H). 13C-NMR δ=−4.2, 21.8, 125.3, 125.4, 125.5, 127.7, 129.6, 129.8, 130.1, 130.4, 130.8, 132.8, 133.5, 138.4, 139.8, 142.0, 148.2, 148.2, 156.4.
Reaction SMILES: [C:1]([O:9][CH3:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C@H:12](CO)[CH:13]([CH3:15])[CH3:14]>[Zn].ClC1C=CC=CC=1>[CH:13]([C@H:12]1[CH2:10][O:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:11]1)([CH3:15])[CH3:14]
Reactant: CC(C)[C@H](N)CO
Reactant: COC(=O)c1ccccc1
Agent: [Zn]
Solvent: Clc1ccccc1
Product: CC(C)[C@H]1COC(c2ccccc2)=N1
Yield: 83 %

Procedure:
Under an argon atmosphere, a mixture of methyl benzoate (1.5 mmol), (L)-valinol (1.8 mmol), Zn4(OCOCF3)6O (0.15 mmol in terms of the number of moles of zinc atom; the number of moles of the zinc compound used in the following Examples is also shown in terms of the number of moles of zinc atom) and chlorobenzene (2.5 mL) was heated under reflux for 12 hours. From the resulting solution, the solvent was removed using an evaporator, and the residues were purified by silica gel column chromatography (hexane/ethyl acetate=10/1 (V/V)) to give (S)-4-isopropyl-2-phenyl-1,3-oxazoline in 83% yield.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[Cl:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[CH:34]=[CH:33][N:32]=[C:31]([Cl:30])[CH:36]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1ccnc(Cl)c1
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: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
To a solution of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (858 mg, 1.733 mmol) and 2-chloropyridine-4-boronic acid (327 mg, 2.080 mmol) in dioxane (14.6 mL) was added Pd(PPh3)4 (160 mg, 0.139 mmol) and 2N K2CO3 (3.6 mL, 7.280 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 90° C. for 6 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H27Cl2N2O3S: 529.1; found: 529.2.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)C.Cl.[N:16]([O-])=[O:17].[Na+]>O>[CH3:2][N:3]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[N:16]=[O:17]
Reactant: CNCCc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(CCc1ccccc1)N=O
Temperature: 70 °C
Yield: 81.6 %

Procedure:
A sample of N-methyl-2-phenylethylamine hydrochloride (6.4 g, 37.3 mmol) was dissolved in water (18 ml), ethanol (11 ml) and 2N hydrochloric acid (4 ml) were introduced and the solution was heated to 70° C. A solution of sodium nitrite (2.6 g, 37.7 mmol) in water (11 ml) was added dropwise to the reaction mixture over 30 min. During the addition the reaction mixture was acidified with 2N hydrochloric acid (4 ml). Cooling was followed by extraction with n-heptane (4×100 ml); the combined extracts were dried (MgSO4) and evaporated in vacuo to provide the N-methyl-N-nitroso-2-phenylethylamine as an oil (5.0 g, 81%) (a ca. 65:35 mixture of apparent geometric isomers), 1H NMR (DMSO-d6) γ 2.98 (3H, s,--CH3), 3.05 (2H, t, PhCH2 --), 4.37 (2H, t, --CH2 --N--), 7.13-7.36 (5 H, m, Ar-H) (major isomer); 2.78 (2H, t, PhCH2 --), 2.98 (3H, s,--CH3), 3.77 (2H, t,--CH2 --N--), 7.13-7.36 (5H, m, Ar-H) (minor isomer).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH:4]([C:12]([OH:14])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH2:21]([N:23]([CH2:24][CH3:25])[C:12]([CH:4]1[CH2:3][C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5]1)=[O:14])[CH3:22]
Reactant: O=C1CC(C(=O)O)Sc2ccccc21
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)C1CC(=O)c2ccccc2S1
Temperature: 0 °C
Yield: 65.1 %

Procedure:
(+−)-4-Oxo-thiochroman-2-carboxylic acid (10.4 g, 50 mmol), prepared as described in T. Okubo et at (Bioorg. Med. Chem. 2004; 12: 3569-3580), in dry DCM (100 ml) was stirred under an atmosphere of nitrogen at room temperature with oxalyl chloride (12.6 g, 100 mmole) and one drop of DMF for 18 h. The reaction was then evaporated in vacuo to a gum and then redissolved in DCM (100 ml), cooled to 0° C. on an ice bath, stirred and treated dropwise with diethylamine (8.03 g, 110 mmol) in DCM (20 ml) over a period of 1 h. The reaction was allowed to warm to room temperature over 1 h and 10% aqueous potassium carbonate solution (100 ml) was added and the reaction mixture vigorously stirred. The DCM solution was separated. The aqueous solution was extracted with two further batches of DCM (100 ml) and the combined extracts were dried over magnesium sulphate. The DCM solution was concentrated in vacuo to give a dark green oil that crystallized on standing. The crystalline solid was triturated with diethyl ether (50 ml) and filtered to give the title compound (50) (8.57 g, 65%) as a pale green solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δ 1.06 (t, J=7.1 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H), 3.0-3.5 (m, 6H), 4.25 (m, 1H), 7.15-7.21 (m, 2H), 7.32-7.39 (m, 1H), 8.10-8.14 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:15]([N:20]([CH2:21][CH3:22])[CH2:18][CH3:19])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCNCC
Reactant: O=C(O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Product: CCN(CC)C(=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Yield: 13 %

Procedure:
The amide was synthesized from 1-(3,4-dichlorophenyl)-cyclohexanecarboxylic acid (232 mg, 0.85 mmol) and diethyl amine using General Procedure G and was isolated in 13% yield as a white solid. HPLC Rt=12.0 min; 1H NMR (400 mHz, CDCl3) 7.38-7.26 (m, 2H), 7.08 (dd, J=2.2, 8.4 Hz, 1H), 3.29 (bs, 2H), 2.84 (bs, 2H), 2.26 (d, J=12.1 Hz, 2H), 1.73-1.54 (m, 7H), 1.29-1.24 (m, 2H), 1.08 (bs, 3H), 0.82 (bs, 3H); 13C NMR (100 mHz, CDCl3) 172.9, 147.2, 133.0, 130.8, 130.4, 127.5, 125.2, 51.2, 42.0, 40.9, 37.3, 26.0, 23.7, 13.4, 12.4; GC-MS (SCOUT) 13.2 min, M+ 327.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][OH:6])[CH3:2].Cl[C:8]([CH3:12])([CH3:11])[C:9]#[CH:10]>C1COCC1.Cl[Cu]>[CH3:11][C:8]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][OH:6])([CH3:12])[C:9]#[CH:10]
Reactant: CCNCCO
Reactant: C#CC(C)(C)Cl
Agent: Cl[Cu]
Solvent: C1CCOC1
Product: C#CC(C)(C)N(CC)CCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 14.3 ml (146.3 mmol) 2-Ethylaminoethanol in 60 ml THF were added 362 mg (3.7 mmol) CuCl, followed by 7.5 g (73.1 mmol) 3-Chloro-3-methyl-1-butyne. The solution was stirred at RT for 2 h, the solvent was removed and the residue dissolved in ether/2M HCl. The phases were separated and after addition of Na2CO3 to the aqueous phase (pH9), it was extracted with ether. The ether phase was dried over Na2SO4 and concentrated. Distillation by Kugelrohr yielded 2-[(1,1-Dimethyl-prop-2-ynyl)-ethyl-amino]-ethanol as colorless oil, MS: 155 (M).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N+:12]([O-])=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>C(O)C.[C].[Pd]>[NH2:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnccc1-n1ccnc1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.9 %

Procedure:
4-(1-Imidazolyl)-3-nitropyridine (2.10 g, 11.0 mmol) was dissolved in 20 ml of ethanol. After the atmosphere was replaced with nitrogen, 0.25 g of 10% palladium-carbon was added thereto. After the atmosphere was replaced with hydrogen, hydrogen addition was conducted with stirring at room temperature for 3 days. Palladium-carbon was removed by filtration and the filtered cake was washed with ethanol. The filtrate and the washings were combined and then concentrated. The residue was purified by silica gel column chromatography [eluent: dichloromethane: methanol=8:1-6:1 (v/v)] to obtain 1.62 g of a light brown solid (yield: 91.6%).
Reaction SMILES: Cl.CN(C)[CH2:4][CH:5]([CH3:15])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])=[O:7].[C-:17]#[N:18].[K+]>O>[C:17]([CH2:4][CH:5]([CH3:15])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])=[O:7])#[N:18]
Reactant: [C-]#N
Reactant: CC(CN(C)C)C(=O)c1ccccc1O
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(CC#N)C(=O)c1ccccc1O
Yield: 93 %

Procedure:
A mixture of 2-(3-dimethylamino-2-methylpropionyl)phenol hydrochloride (2.70g), potassium cyanide (1.3g) and water (50 ml) was heated under reflux for 2 hours. The mixture was cooled, neutralised and extracted with chloroform. The extracts were dried (MgSO4) and the solvent was evaporated and purified by chromatography on a silica column to give 2-(3-cyano-2-methylpropionyl)phenol as an orange oil (1.95g).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]([CH3:24])([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])[CH2:13][CH2:12]1)=[O:10])[CH3:7].[CH:25](=O)[CH3:26]>CO>[CH3:7][C:6]([CH3:24])([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][CH2:25][CH3:26])[CH2:13][CH2:12]1)=[O:10])[CH3:5]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Sodium cyanoborohydride (1.6 g) is added to a 0° solution of 1-[1,1-dimethylethoxycarbonyl]-4-(2-aminophenyl)piperazine (PREPARATION 13, 6.52 g) and acetaldehyde (1.48 ml) dissolved in methanol (65 ml). After 3 hr the reaction mixture is partially concentrated under reduced pressure. Then it is diluted with chloroform, washed with saturated aqueous sodium bicarbonate, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, Rf =0.62 (ethyl acetate/hexane, 1/1), NMR (300 MHz, CDCl3) 7.04, 6.95, 6.66, 4.59, 3.70-3.50, 3.15, 2.82, 1.49 and 1.28δ.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[CH2:22][CH:8]1[CH2:9][O:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][N:12]=1>C(O)C>[OH:7][CH:8]([CH2:22][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH2:9][O:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][N:12]=1
Reactant: C1COCCN1
Reactant: c1ccc(-c2cc(OCC3CO3)no2)cc1
Solvent: CCO
Product: OC(COc1cc(-c2ccccc2)on1)CN1CCOCC1
Yield: 89.2 %

Procedure:
17.6 g of morpholine were added to a solution of 40.0 g of 3-(2,3-epoxypropoxy)-5-phenylisoxazole (prepared as described in Preparation 4) in 400 ml of ethanol, and the mixture was heated under reflux for 5 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting solid residue was recrystallized from ethyl acetate, to give 50.0 g (yield 89.2%) of the title compound as colorless columnar crystals, melting at 123°-124° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][C:36]([F:48])([F:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])[C:29]([O:31]CC)=[O:30])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:34][CH2:35][C:36]([F:48])([F:47])[C:37]([F:45])([F:46])[C:38]([F:43])([F:44])[C:39]([F:40])([F:41])[F:42])[C:29]([OH:31])=[O:30])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCCCCCCCC1c2ccc(O)cc2OCC1(C)c1ccc(O)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Yield: 80.7 %

Procedure:
Ethyl 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoate (1.10 g, 1.570 mmol) and potassium hydroxide (880 mg, 15.70 mmol) were added to a methanol/water mixture (2:1, 15 ml), followed by heating under reflux for 4 hours. After the reaction mixture was neutralized with 1N hydrochloric acid, the solvent was distilled off under reduced pressure. The residue was diluted with water, adjusted to pH 2-3 with 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4) to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid (852 mg, Yield 81%) as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[C:13](=[O:14])[N:12]([CH2:15][CH3:16])[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl>[Br:1][C:2]1[C:13](=[O:14])[N:12]([CH2:15][CH3:16])[C:5]2[N:6]=[C:7]([S:10]([CH3:11])=[O:25])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: CCn1c(=O)c(Br)cc2cnc(SC)nc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCn1c(=O)c(Br)cc2cnc(S(C)=O)nc21
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-8-ethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3, 0.96 g, 3.19 mmol) in dichloromethane (40 mL) was added 3-chloroperbenzoic acid (77%, 0.68 g, 3.04 mmol) in dichloromethane (10 mL) at 0-5° C. and the mixture was stirred at 0-5° C. for 1 h. The reaction mixture was washed with 10% sodium bicarbonate solution (1×20 mL) and in water (1×20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The title compound was obtained as a pale yellow solid (0.98 g, 3.10 mmol, 97%). ESMS m/z 316 (M+H)+.