Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C(#N)C>[O:28]([CH2:27][CH2:26][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:2]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1nccc2cc(OC3CCCNC3)ccc12
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Nc1nccc2cc(OC3CCCN(CCOc4ccccc4)C3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
To a solution of 6-(piperidin-3-yloxy)isoquinolin-1-ylamine (30 mg, 123 μmol) in DMF (1 ml) was added potassium carbonate (18 mg, 129 μmol) followed by a solution of (2-bromoethoxy)benzene (26 mg, 129 μmol) in acetonitrile (0.5 ml). The mixture was stirred for 16 h at ambient temperature, then the solvent removed in vacuo and aqueous sodium hydrogen carbonate added. The mixture was extracted with chloroform/iso-propanol (3:1), dried (magnesium sulphate) and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC to give 6-[1-(2-phenoxyethyl)piperidin-3-yloxy]-isoquinolin-1-ylamine (12.5 mg) El-MS: m/z=364.8 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[S:31][C:30]([S:32]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)(=[O:34])=[O:33])=[CH:29][CH:28]=1>>[CH3:41][N:38]1[CH2:37][CH2:36][N:35]([S:32]([C:30]2[S:31][C:27]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=5)=[N:8][C:7]=34)=[CH:28][CH:29]=2)(=[O:34])=[O:33])[CH2:40][CH2:39]1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: CN1CCN(S(=O)(=O)c2ccc(C#Cc3cnn4c(C(F)(F)F)cc(-c5cccc(C(F)(F)F)c5)nc34)s2)CC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and 1-(5-bromo-thiophene-2-sulfonyl)-4-methyl-piperazine (example B.50) (163 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (210 mg, 70%). MS (EI) 599.1 [(M)+]; mp 191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16].C(N(CC)CC)C>C(C(C)=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:15]([NH:14][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1c(Cl)cc(Cl)c2cccnc12
Reactant: CCOC(=O)CN=C=O
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCOC(=O)CNC(=O)Oc1c(Cl)cc(Cl)c2cccnc12
Temperature: 25 °C
Reaction time: 42 h

Procedure:
5,7-Dichloro-8-hydroxyquinoline (21.4 g), ethyl isocyanatoacetate (21.3 g) and triethylamine (1.0 ml) were mixed together in 400 ml of methyl ethyl ketone and stirred at room temperature for about 42 hours resulting in the precipitation of a white crystalline solid. This solid was removed from the reaction mixture by filtration and was determined to be the desired ethyl N-(((5,7-dichloro-8-quinolinyl)oxy)carbonyl)glycinate, m.p. 119.5° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][CH2:19][C:20]#[CH:21].[OH-].[Na+]>>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][CH2:19][C:20]#[C:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C#CCOC1CCCCO1
Reactant: CCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCC#CCOC1CCCCO1

Procedure:
A process for preparing the sex pheromone of Lymantria dispar L. effectively which comprises the steps of reacting 1-bromodecane and propargyl alcohol tetrahydropyranylether in the presence of sodium hydroxide to give 1-tetrahydropyranyloxy-2-tridecyne, treating the tetrahydropyranyloxy-2-tridecyne with p-toluenesulfonic acid to give 2-tridecyn-1-ol, catalystic-hydrogenating the 2-tridecyn-1-ol in the presence of Lindlar catalyst to give (Z)-2-tridecen-1-ol, oxidizing the (Z)-2-tridecen-1-ol with peroxide to give (±)-cis-2,3-epoxy-1-tridecanol, reacting the (±)-cis-2,3-epoxy-1-tridecanol with acid anhydride in the presence of hydrolase in an organic solvent for a stereoselective acylation and recovering unreacted optically active (2R, 3S)-cis-2,3-epoxy-1-tridecanol after the acylation, reacting the optically active (2R, 3S)-cis-2,3-epoxy-1-tridecanol with toluenesulfonylchloride to give (2R, 3S)-cis-1-p-toluenesulfoxy-2,3-epoxytridecane, and reacting the (2R, 3S)-cis-1-p-toluenesulfoxy-2,3-epoxytridecane with di(4-methylpentyl) lithium copper reagent to yield (7R, 8S)-cis-2-methyl-7,8-epoxyoctadecane which is the sex pheromone of Lymantria dispar L.
Reaction SMILES: [NH2:1][C@H:2]([CH3:35])[C:3]([C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:30][CH2:31][CH2:32][CH2:33][CH3:34])([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19])[OH:4].[CH:36](=O)[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]>C(O)C.C1(C)C=CC=CC=1>[CH:36](=[N:1][C@H:2]([CH3:35])[C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH2:18][CH3:19])([C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:30][CH2:31][CH2:32][CH2:33][CH3:34])[OH:4])[C:37]1[C:38](=[CH:40][CH:41]=[CH:42][CH:43]=1)[OH:39]
Reactant: O=Cc1ccccc1O
Reactant: CCCCOc1ccc(C(C)(C)C)cc1C(O)(c1cc(C(C)(C)C)ccc1OCCCC)[C@@H](C)N
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(C(C)(C)C)cc1C(O)(c1cc(C(C)(C)C)ccc1OCCCC)[C@@H](C)N=Cc1ccccc1O
Yield: 99.5 %

Procedure:
0.968 g (2.0 mmol) of (R)-2-amino-1,1-di(2-butoxy-5-t-butylphenyl)-propanol and 0.244 g (2.0 mmol) of salicylaldehyde were dissolved in 20 ml of ethanol and 20 ml of toluene, the solution was heated at reflux for 1 hour. The solvent was distilled off from the reaction mixture and dried to obtain 1.17 g of (R)-N-salicyliden-2-amino-1,1-di(2-butoxy-5-t-butylphenyl)-propanol as a yellow solid.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.B(O)(O)O.C(N(CC)CC)C.[NH2:19][CH:20]1[C:35](=[O:36])[N:22]2[C:23]([C:32]([OH:34])=[O:33])=[C:24]([CH2:27]OC(=O)C)[CH2:25][S:26][C@H:21]12>O>[NH2:19][CH:20]1[C:35](=[O:36])[N:22]2[C:23]([C:32]([OH:34])=[O:33])=[C:24]([CH2:27][S:1][C:2]3[S:3][C:4]([CH3:7])=[N:5][N:6]=3)[CH2:25][S:26][C@H:21]12
Reactant: Cc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: OB(O)O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1

Procedure:
A suspension of 40 g (0.30 mole) of 2-mercapto-5-methyl-1,3,4-thiadiazole (TD) in 3.15 liters of water, with 30 g of boric acid and 30.4 ml (≃0.217 mole) of triethylamine was heated to 70/72° C. While the mixture was being vigorously stirred, at the same temperature, one 40 g shot (0.147 mole) of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (92%) was added.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15](\[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=CC=1)([O-])=O.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH:32]=1>O1CCCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22](/[C:15](/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:14]\[CH:13]=[CH:12]\[C:11]([NH:41][CH2:40][CH2:39][CH2:38][CH2:37][C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][CH:26]=1
Reactant: NCCCCc1cccnc1
Reactant: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccnc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(/C(=C\C=C\C(=O)NCCCCc2cccnc2)c2cccnc2)cc1
Yield: 63.5 %

Procedure:
As before in Example 134, a solution of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.61 g) and 3-pyridinebutanamine (0.61 g) in tetrahydrofuran (20 mL) was stirred overnight at room temperature. After the usual workup. the crude product was crystallized form ethyl acetate to provide 1.05 g of (E,E)-5-(4-methoxyphenyl)-5-(3-pyridinyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide, mp 121°-123° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C>[C:19]([O:18][C:16](=[O:17])[CH2:15][NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(CN)OC
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CNCC(=O)OC(C)(C)C)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a mixture of 2,2-dimethoxyethylamine (15 g, 143 mmol), anhydrous potassium carbonate (20 g, 145 mmol) and DMF (140 mL) was added tert-butyl bromoacetate (11.5 mL, 71.2 mmol). After stirring at room temperature for 2 hours, another portion of tert-butyl bromoacetate (11.5 mL, 71.2 mmol) was added to the mixture, which was stirred overnight at room temperature. To the reaction mixture was added ice-water (140 mL). The mixture was extracted with EtOAc. The organic layer was washed with sat. NaCl, dried over Na2SO4, filtered and evaporated. The residue was subjected to distillation under reduced pressure to give the title compound as a colorless oil (6.61 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[CH2:30]([N:32]([CH2:37][CH3:38])[C:33](=[O:36])[CH2:34][OH:35])[CH3:31]>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([O:35][CH2:34][C:33]([N:32]([CH2:37][CH3:38])[CH2:30][CH3:31])=[O:36])=[N:3][C:4]=1[O:28][CH3:29])(=[O:10])=[O:11]
Reactant: CCN(CC)C(=O)CO
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Product: CCN(CC)C(=O)COc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OC)n1

Procedure:
Prepared as for Example 115b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (Example 55a) (0.35 g) and N,N-diethyl-2-hydroxyacetamide (0.13 g). Yield 0.2 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15]([NH:20][C@H:21]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]2)[CH:14]=[CH:13]3)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15]([NH:20][C@H:21]2[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]2)[CH:14]=[CH:13]3)=[N:31][OH:32])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccc(F)cc1)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccc(F)cc1)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Yield: 59 %

Procedure:
A stirred suspension of (4-fluoro-phenyl)-[2-((R)-indan-1-ylamino)-quinolin-6-yl]-methanone (100 mg, 0.26 mmol), hydroxylamine hydrochloride (55 mg, 0.79 mmol) and sodium carbonate (83 mg, 0.78 mmol) in ethanol (1 ml) was heated under reflux conditions for 17 h, the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (3×75 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/ethyl acetate) and crystallization (ethyl acetate/heptane) to yield the title compound as white solid (61 mg, 59%).
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][N:16]2[C:20](=[O:40])[C:21]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25](S(C)(=O)=O)[N:24]=3)[N:15]12)=[O:13].O>C1COCC1>[CH3:10][O:11][C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]2[C:20](=[O:40])[C:21]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([O:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:24]=3)[N:15]12)=[O:13]
Reactant: COC(=O)C1CCCn2c(=O)c(-c3ccc(F)cc3)c(-c3ccnc(S(C)(=O)=O)n3)n21
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCCn2c(=O)c(-c3ccc(F)cc3)c(-c3ccnc(Oc4ccccc4)n3)n21
Yield: 54 %

Procedure:
NaOH (0.112 g, 2.8 mmol) is added to a solution of phenol (0.316 g, 3.36 mmol) in THF (100 mL). 2-(4-Fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-1-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester, 32, (0.5 g) is dissolved in THF (50 mL) and added dropwise to the solution over 5 minutes. The resulting mixture is stirred at room temperature for 8 hours after which water (20 mL) is added. The solution is extracted with ethyl acetate (100 mL the organic layer washed with brine (50 mL) and concentrated in vacuo to afford 0.278 g (54% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.75 (m, 2 H), 1.97 (m 1 H), 2.42 (d, J=12.8 Hz, 1 H), 3.27 (m, 1 H), 3.27 (m, 1 H), 3.6 (s, 3 H), 4.5 (br d, J=12.8 Hz, 1 H), 5.25 (m, 1 H), 6.87 (d, J=5.7 Hz, 1 H), 7.05 (m, 2H), 7.23 (m, 2 H), 7.35 (m, 3 H), 7.52 (m, 2 H), 8.42 (d, J=5.7 Hz, 1 H): exact mass calc. for C25H21FN4O4 460.46, MS-ESI (M+1) 461.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>>[CH2:25]([O:24][P:23]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([F:22])([F:21])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])([O:27][CH2:28][CH3:29])=[O:30])[CH3:26]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Temperature: 150 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
A mixture of 8.24 g of 1-bromo-8-(nonafluorobutyl)octane and 8.31 g of triethyl phosphite was heated at 150° C. After 15 hr an additional 4.30 g of triethyl phosphite was added, and heating was continued for 4 hr. Diethyl ethylphosphonate and other volatiles were removed by distillation, b.p. 30-50° C. at 0.05 torr (7 Pa). Bulb-to-bulb distillation of the concentrate provided 8.72 g of 1-(diethylphosphono)-8-(nonafluorobutyl)octane as a clear, colorless liquid, b.p. 115-125° C. at 0.08 torr (11 Pa).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[C:13]3[C:12]([C:24]3[CH:28]=[CH:27][O:26][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO.O>[O:26]1[CH:27]=[CH:28][C:24]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[NH:10][CH:11]=2)=[CH:25]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccoc2)c2cc(-c3cccs3)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1csc(-c2cnc3[nH]cc(-c4ccoc4)c3c2)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a solution of 33 (28.3 mg, 0.0696 mmol) in EtOH (1.4 mL), was added 10% aqueous NaOH (0.67 mL), and the reaction mixture refluxed (oil bath 110° C.) for 0.5 h. The mixture was diluted with water (1.4 mL), and stirred for an additional 0.5 h at r.t. The precipitate was filtered off, washed with water, and dried under high vacuum to afford 34 as tan solid (15.8 mg, 85%); 1H NMR (400 MHz; CDCl3) δ 6.72 (dd, J=1.8, 0.8 Hz, 1H), 7.14 (dd, J=5.1, 3.6 Hz, 1H), 7.32-7.36 (m, 2H), 7.48 (d, J=2.5 Hz, 1H), 7.55 (t, J=1.7 Hz, 1H), 7.82 (m, 1H), 8.23 (dd, J=2.0, 0.4 Hz, 1H), 8.65 (d, J=2.0 Hz, 1H), 9.67 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>[Cu](I)I.CN(C=O)C>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccc2ccc(Br)cc2n1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cc1ccc2ccc(C#C[Si](C)(C)C)cc2n1
Temperature: 110 °C
Yield: 80.8 %

Procedure:
In a sealed tube were introduced 7-bromo-2-methyl-quinoline (500 mg, 2.25 mmol, 1.0 eq), PdCl2(PPh3)3 (79 mg, 0.11 mmol, 5% mol), copper iodide (21 mg, 0.11 mmol, 5% mol), and triphenylphosphine (106 mg, 0.39 mmol, 20% mol). Then, DMF (5 mL) was added followed by diethylamine (3.5 mL, 34 mmol, 15 eq) and trimethylsilylacetylene (350 μL, 2.5 mmol, 1.1 eq). The mixture was heated at 110° C. overnight. After cooling down the solvent was evaporated and the crude product was purified by column chromatography (Florisil, Cyclohexane-EtOAc 95:5) to afford 2-methyl-7-trimethylsilanylethynyl-quinoline as a white solid (435 mg, 81%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[NH2:20])=[C:10]([C:22](OCC)=[O:23])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC1C=CC=CN=1>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]2[C:12](=[O:21])[C:11]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:8][NH:9][C:10]=3[C:22](=[O:23])[NH:20][C:14]=2[CH:15]=1
Reactant: CCOC(=O)c1[nH]nc(-c2ccccc2)c1C(=O)c1ccc(Cl)cc1N
Agent: Oc1ccccn1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)c2c(-c3ccccc3)n[nH]c12
Yield: 51.6 %

Procedure:
A mixture of ethyl 3-phenyl-4-(4-chloro-2-aminobenzoyl)-1H-pyrazole-5-carboxylate (0.84 g, 2.28 mmol) and 2-hydroxy-pyridine (0.217 g, 2.28 mmol) in toluene (12 mL) was distilled at 160° C. until all the toluene was removed. The residue was heated at the same temperature for 18 hours. The reaction residue was washed with water to remove the 2-hydroxy-pyridine. The insoluble material was added to methanol (225 mL) and heated to boiling. Ethyl acetate (100 mL) was added and the solution heated for an additional 2 minutes, then concentrated to 100 mL. The solution was filtered to remove some insoluble material and the filtrate concentrated via rotovap until a precipitate formed which was filtered to give the title compound as a tan solid (0.381 g, 51%, mp 328.1-330.9° C.).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][N:14]1[C@H:28]2[C@@H:18]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29]=3[C:26]([CH2:27]2)=[CH:25][NH:24]4)[CH2:17][C:16](=O)[CH2:15]1>[Pd]>[CH3:13][N:14]1[C@H:28]2[C@@H:18]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:29]=3[C:26]([CH2:27]2)=[CH:25][NH:24]4)[CH2:17][CH:16]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[N:7][CH:8]=2)[CH2:15]1
Reactant: CC(C)(C)Oc1ccc(N)cn1
Reactant: CN1CC(=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Agent: [Pd]
Product: CN1CC(Nc2ccc(OC(C)(C)C)nc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21

Procedure:
The following compounds (isomers Ia and Ib) are obtained in a manner analogous to that described in Example 3, from 2-tert.butoxy-5-aminopyridine and 6-methyl-8-oxo-ergoline in the presence of palladium:
Reaction SMILES: [CH3:1][C:2](Cl)([CH2:4][CH2:5][C:6]([CH3:9])(Cl)[CH3:7])[CH3:3].[CH2:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)CCl>[CH2:11]([C:13]1[CH:18]=[C:17]2[C:16]([C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][C:6]2([CH3:9])[CH3:7])=[C:15]([OH:19])[CH:14]=1)[CH3:12]
Reactant: CCc1cccc(O)c1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
Next, 2,5-dimethyl-2,5-dichlorohexane (183 g, 1 mol) is stirred with 3-ethylphenol (146.4 g, 1.2 mol) and aluminum chloride (4 g) is added. The mixture is heated at 95° C., with stirring, for 1.5 hr, after which ethylene dichloride (100 ml) is added, and then the heating continued. After 1 hr, the mixture is cooled to 20° C., and poured onto an ice water/hydrochloric acid mixture (150 ml, 10% HCl solution). The mixture is then extracted with toluene (500 ml), the organic layer separated, washed with brine (3×50 ml) and dried (Na2SO4). The solvent is removed by distillation and the residue crystallized from a hexane/benzene solvent mixture to give 7-ethyl-1,1,4,4-tetramethyl-5-hydroxy-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[C:42]1([CH:48]2[CH2:52][CH2:51][NH:50][CH2:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[H-].[Na+]>CN(C)C=O.COC(C)(C)C>[CH3:40][O:39][CH2:38][CH2:37][CH2:36][N:32]1[C:31]2[CH:41]=[C:27]([CH2:26][O:25][CH:10]3[CH:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:50]5[CH2:51][CH2:52][CH:48]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)[CH2:49]5)=[CH:4][CH:5]=4)[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:11]3)[CH:28]=[CH:29][C:30]=2[O:35][CH2:34][CH2:33]1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CN4CCC(c5ccccc5)C4)cc3)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The stirred solution of 0.0435 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270b) and 0.0155 g of 3-phenylpyrrolidine in 0.5 ml of N,N-dimethylformamide is admixed at 0° C. with 0.0076 g of sodium hydride dispersion (60% in oil). The reaction mixture is stirred at 0° C. over 15 minutes, then at room temperature for 1 hour, and subsequently diluted with 80 ml of tert-butyl methyl ether. The mixture is washed with 20 ml of water, then 10 ml of brine, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rt=4.72.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#N)N=1)(=[O:3])C.[CH:12](=O)[C:13]1C=CC=CC=1>>[C:8]1([CH:9]=[CH:4][CH:1]=[O:3])[CH:7]=[CH:6][CH:10]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1cccc(C#N)n1
Product: O=CC=Cc1ccccc1

Procedure:
reacting said 2-acetyl-6-cyanopyridine with a benzaldehyde for a time period and under conditions sufficient to form the corresponding 3-phenyl-2-propen-1-one; and