Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of 7-hydroxy-3,4-dihydro-quinolin-2(1H)-one (1.50 g) in N,N-dimethylformamide (10 ml), potassium carbonate (1.85 g) and methyl iodide (0.63 ml) were added and stirred overnight at room temperature. Insoluble materials were filtered off and the filtrate was concentrated. The resulting residue was diluted with ethyl acetate and then washed sequentially with water, saturated aqueous sodium thiosulfate:brine (1:1) and brine, followed by distilling off the solvent under reduced pressure. The resulting residue was diluted with n-hexane, and the crystal was collected by filtration to give 7-methoxy-3,4-dihydroquinolin-2(1H)-one (1.38 g) as a colorless crystal. To a solution of 7-methoxy-3,4-dihydroquinolin-2(1H)-one thus obtained (1.38 g) in tetrahydrofuran (30 ml), lithium aluminum hydride (592 mg) was added under ice cooling, heated under reflux for 4.5 hours, and then stirred overnight at room temperature. The reaction mixture was diluted with 28% aqueous ammonia under ice cooling and filtered to remove insoluble materials. The filtrate was evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=20:1 to 9:1) to give the titled compound, i.e., 7-methoxy-1,2,3,4-tetrahydroquinoline (1.18 g) as a yellow oil.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[CH:11][C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:28])([CH3:27])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1.CN(C=O)C.[Br:40]N1C(=O)CCC1=O>O>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][C:4]([CH:7]2[CH:26]=[C:25]3[C:10](=[C:11]([Br:40])[C:12]4[CH:13]=[C:14]5[C:22]([C:23]([CH3:27])([CH3:28])[C:24]=43)=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]5)[CH:9]=[CH:8]2)=[CH:3][CH:2]=1
Reactant: CC1(C)C2=C(C=C3C=CC(c4ccc(-c5ccccc5)cc4)C=C32)C=C2N=c3ccccc3=C21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccc(-c4ccccc4)cc3)C=C12
Temperature: 70 °C
Reaction time: 7 h
Yield: 69.5 %

Procedure:
The resulting 10-(biphenyl-4-yl)-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (42.5 g) and DMF (2.5 L) were added to a reaction vessel, and the mixture was heated up to 70° C. and dissolved. After cooled to a room temperature, N-bromo-succinimide (17.4 g) was added, and the mixture was stirred for 7 hours. Water (2.5 L) was added, and filtration was performed to obtain a white powder of 10-(biphenyl-4-yl)-7-bromo-12,12-dimethyl-10,12-dihydroindeno[2,1-b]carbazole (34.9 g; yield 69.5%).
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].[Br-].[Na+].C([Li])CCC.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1.O>[C:23]1([CH2:22][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)c1ncccc1CCc1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Tetrahydrofuran (125 mL), N-(1,1- dimethylethyl)-3-methyl-2-pyridine carboxamide (1 equivalent) and sodium bromide (1.3 g) are charged and cooled to -40° C. under nitrogen. Two equivalents of nbutyllithium are then added over 40 minutes. When half the n-butyllithium is added the mixture turns purple. Benzyl chloride (1.05 equivalents) is then added dropwise (1:1 solution in tetrahydrofuran) over 40-50 minutes while the temperature is maintained at -40° C. After 30 minutes at -40° C., the mixture is diluted with water (250 ml) and the organic phase separated. This phase is dried over sodium sulphate and the solvent removed yielding an oil from which solid product may crystallize. Product yield of 94% determined by internal standard assay on gas chromatograph.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([O:13]C(N(C)C)N(C)C)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[O:13])[N:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cccc(F)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccc(F)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Fluoro-6-methylpyridine (14.4 g, 0.13 mol) and tert-butoxybis(dimethylamino)methane (Bredereck's reagent; 34.9 g, 0.20 mol) are heated at 140° C. for 24 h. The reaction is cooled and diluted with THF (100 mL). Sodium periodate (75 g) in water (400 mL) is added at 0-5° C., and the reaction mixture is then stirred for 24 h at room temperature. The precipitate is filtered through celite, and the filtrate extracted 5× with diethyl ether. The combined ether layers are washed with water, brine, and dried (MgSO4). Most of the solvent is removed by concentration at 0° C. (by keeping ice in the bath) to provide 2-Fluoropyridine-6-carboxaldehyde.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[S:22][C:21]([C:23](O)=[O:24])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:19]=3[CH:32]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>ClCCl.CO>[OH:37][CH:35]([CH3:36])[CH2:34][NH:33][C:23]([C:21]1[S:22][C:18]2[CH:17]=[CH:16][C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)(=[O:12])=[O:13])=[CH:32][C:19]=2[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]
Reactant: CC(O)CN
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)O)c(-c4ccccc4)c3c2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(O)CNC(=O)c1sc2ccc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2c1-c1ccccc1
Yield: 17 %

Procedure:
According to Step 1 after reaction of 5-(4-tert-Butylbenzenesulfonylamino)-3-phenyl-1-benzothiophene-2-carboxylic acid (155 mg, 0.33 mmol) with 1-amino-2-propanol (0.027 mL, 0.35 mmol) and subsequent chromatographic purification (silica gel, dichloromethane/methanol (0-10% methanol)), the desired compound is obtained at 17% yield (2 mg).
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:28]I>C1COCC1.CCOCC>[C:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][N:23]([S:24]([CH3:27])(=[O:26])=[O:25])[CH3:28])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CNS(C)(=O)=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a stirred suspension of sodium hydride (60% in oil, 113 mg, 2.82 mmol) in THF (20 mL) at 0° C. under nitrogen was added a solution of 1-Boc-4-[2-(methanesulfonylamino-methyl)-phenyl]-piperazine (0.99 g, 2.68 mmol) in THF (5 mL). The mixture was stirred for about 1 hour at room temperature. It then was cooled back to 0° C. and treated with methyl iodide (0.184 mL, 2.95 mmol). After stirring for about 20 hours, the reaction mixture was diluted with ether (150 mL) and then quenched by addition of saturated aqueous ammonium chloride (50 mL). The organic phase was separated, washed with water (50 mL) and brine (50 mL) and then dried over magnesium sulfate. Concentration under reduced pressure followed by silica gel chromatography (30% ethyl acetate in hexanes) afforded the title compound (0.96 g, 94%) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][S:6](Cl)(=[O:8])=[O:7].[NH2:13][C:14]1[C:15](=[O:29])[N:16]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([CH3:20])=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][S:6]([NH:13][C:14]1[C:15](=[O:29])[N:16]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)Cc1cccc(Cl)c1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Product: Cc1ccc(NS(=O)(=O)Cc2cccc(Cl)c2)c(=O)n1CC(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 3-chlorobenzylsulfonyl chloride (113 mg, 0.5 mmol), as prepared in the preceding step, and 3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (120 mg, 0.5 mmol), as prepared in step 3 of Example 1, using the procedure in step 4 of Example 1, as a white solid (180 mg, 84%). 1H-NMR (300 MHz, CDCl3) δ7.37 (d, J=7.6 Hz, 1H), 7.30 (m, 4H), 7.20 (s, 1H), 6.02 (d, J=7.7 Hz, 1H), 4.78 (s, 2H), 4.27 (s, 2H), 2.27 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][C:16](=[O:18])[NH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:21][S:22][CH2:23][CH2:24]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:20][C:2]([F:1])([F:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][C:16](=[O:18])[N:15]([CH2:24][CH2:23][S:22][CH3:21])[N:14]=2)=[CH:9][CH:8]=1
Reactant: CSCCCl
Reactant: O=c1[nH]nc(-c2ccc(OCCCC(F)(F)F)cc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCn1nc(-c2ccc(OCCCC(F)(F)F)cc2)oc1=O
Temperature: 90 °C
Yield: 67.6 %

Procedure:
2 g of 5-[4-(4,4,4-trifluorobutoxy)phenyl]-1,3,4-oxadiazol-2(3H)-one, 1.14 g of 2-chloroethyl methyl sulphide, 2.4 g of potassium carbonate and 30 ml of dimethylformamide are introduced into a 50 ml three-necked round-bottomed flask. The reaction mixture is heated to 90° C. and is maintained at this temperature overnight, then poured into water. The precipitate formed is collected by filtration, washed with water and taken up in ethyl acetate. The solution is dried over sodium sulphate and the solvent is then evaporated off. After recrystallization in diisopropyl ether, 1.7 g of product are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[O:13][C:12](=[O:14])[NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].IC.[CH3:19]N(C)C=O.[H-].[Na+]>O>[CH3:19][N:11]1[N:10]=[C:9]([CH2:8][C:7]2[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:13][C:12]1=[O:14]
Reactant: CN(C)C=O
Reactant: O=c1[nH]nc(Cc2ccc([N+](=O)[O-])cc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1nc(Cc2ccc([N+](=O)[O-])cc2)oc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a mixture of 5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-one (1.0 g), iodomethane (0.97 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.20 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-methyl-5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-one as colorless crystals (0.75 g, yield 71%) from a fraction eluted with hexane-ethyl acetate (3:1-2:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]([F:26])=[C:17]([CH:25]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CC(C)([O-])C.[K+]>CS(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:14]3[C:13]([Cl:12])=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[C:16]([F:26])[CH:15]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OC2CCC3(CC2)OCCO3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.1 %

Procedure:
To a mixture of 1,4-dioxaspiro[4.5]decan-8-ol (2.40 g, 15.20 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (3.78 g, 15.20 mmol) in anhydrous dimethyl sulfoxide was added potassium tert-butoxide (2.56 g, 22.80 mmol) and the reaction mixture was stirred for 16 hours at ambient temperature. After dilution with ethyl acetate (200 mL), the organic phase was washed with water (3×10 mL), brine (10 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by silica gel column chromatography using 0-30% ethyl acetate in hexanes as eluent to afford the title compound as a colorless oil (0.709 g, 12%): 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=7.8 Hz, 1H), 6.64 (d, J=12.3 Hz, 1H), 4.53-4.46 (m, 1H), 3.97-3.92 (m, 4H), 2.04-1.58 (m, 8H), 1.55 (d, J=1.0 Hz, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(N(CC)CC)C.[I:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([I:28])=[CH:30][CH:31]=3)[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(I)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(6-Chloronaphth-2-ylsulphonyl)piperazine (0.65 g, 2.1 mmol) was dissolved in dichloromethane (50 mL) and triethylamine (2.9 mL, 21 mmol) was added at room temperature. 4-Iodobenzoyl chloride (0.56 g, 2.1 mmol) was added as a solid in one portion and the reaction mixture stirred for one hour at room temperature. The reaction mixture was concentrated in vacuo, then separated between EtOAc (100 mL) and saturated sodium hydrogen carbonate solution (100 mL). The EtOAc layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The resulting white solid was subjected to chromatography (SiO2: 50% EtOAc/Hexane) to yield 1-(6-chloronaphth-2-ylsulphonyl)-4-(4-iodobenzoyl)piperazine as a white solid (097 g); 1H NMR (DMSO-d6) δ=3.05 ppm (s,4H), δ=3.53 ppm (s,4H), δ=7.11 ppm & 7.74 ppm (dd,4H), δ=7.65 to 7.84 ppm (m,2H), δ8.10 ppm to 8.28 ppm (m,3H), δ=8.47 ppm (s,1H); MS (M+H)+ 540.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:17]([C:18]([O:20]CC)=O)=[N:16][N:15]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[C:14](=[O:29])[C:9]=3[N:10]([CH3:13])[C:11]=2[CH:12]=1>ClCCl.CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:17]([C:18]([NH:2][CH3:1])=[O:20])=[N:16][N:15]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[C:14](=[O:29])[C:9]=3[N:10]([CH3:13])[C:11]=2[CH:12]=1
Reactant: CCOC(=O)c1nn(-c2cccnc2)c(=O)c2c1c1ccc(F)cc1n2C
Reactant: CN
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1nn(-c2cccnc2)c(=O)c2c1c1ccc(F)cc1n2C

Procedure:
A stream of gaseous methylamine is introduced into a solution of 0.28 g (0.76 mmol) of ethyl 7-fluoro-5-methyl-4-oxo-3-(pyridin-3-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate (obtained in stage 4.1.) in 30 ml of dichloromethane and 70 ml of methanol. Stirring is maintained for 4 h. The reaction medium is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluent: dichloromethane/methanol: 100/0 to 90/10). The solid obtained is recrystallized from a mixture of dichloromethane and ethyl acetate.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[C:29]([O:33][C:34](=[O:52])[CH2:35]P(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O)([CH3:32])([CH3:31])[CH3:30].[S:53]1[C:57]([CH:58]=O)=[CH:56][C:55]2[CH:60]=[CH:61][CH:62]=[CH:63][C:54]1=2>C1COCC1>[C:29]([O:33][C:34](=[O:52])[CH:35]=[CH:58][C:57]1[S:53][C:54]2[CH:63]=[CH:62][CH:61]=[CH:60][C:55]=2[CH:56]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=Cc1cc2ccccc2s1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=Cc1cc2ccccc2s1
Reaction time: 3 h
Yield: 74.3 %

Procedure:
Potassium bis(trimethylsilyl)amide (5.4 g, 0.027 mol) was added to a solution of 18-Crown-6 (13.7 g, 0.052 mol) and (diphenoxy-phosphoryl)-acetic acid tert-butyl ester (9.4 g, 0.027 mol) in dry THF (120 mL) at −780C. After 30 minutes of stirring at this temperature, benzo[b]thiophene-2-carbaldehyde (4.0 g, 0.024 mol) was added and the reaction was stirred for 3 hours at −780C after which the reaction was quenched with saturated ammonium chloride (200 mL). The reaction mix was allowed to come to room temperature and was extracted with ethyl acetate (3×200 mL) and the combined organic extracts were washed with 10% HCl (200 mL), brine (200 mL), and dried over MgSO4. The solvent was evaporated in vacuo leaving the crude product that was purified by column chromatography (SiO2) using a 5-40% ethylacetate-hexane gradient to afford the subtitle compound (4.64 g, yield: 74%). MS calculated for C15H16O2S+H: 261, observed: 261.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH:9]=2)[NH:4]1.[F:21][C:22]([F:35])([F:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1/[CH:29]=[CH:30]/[C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:2]=[C:3]1[C:11]2([CH2:16][CH2:15][N:14]([C:31](=[O:32])/[CH:30]=[CH:29]/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[C:22]([F:34])([F:35])[F:21])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH:9]=2)[NH:4]1
Reactant: COC(=O)c1ccc2c(c1)C1(CCNCC1)C(=O)N2
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)C1(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of methyl 2-oxospiro[indoline-3,4′-piperidine]-5-carboxylate hydrochloride (400 mg, 1.46 mmol) in anhydrous CH2Cl2 (10 mL) was added (E)-3-(2-(trifluoromethyl)phenyl)acrylic acid (315 mg, 1.46 mmol), HOBt (394 mg, 2.92 mmol), EDCI (576 mg, 2.92 mmol) and DIEA (942 mg, 7.30 mol) at 0° C. and then stirred overnight at rt under N2. Then the reaction mixture was washed with 1 N aq HCl and water. The organic layer was dried over Na2SO4, filtered and concentrated to afford a residue, which was purified by preparative TLC to give (E)-methyl 2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxylate (328 mg, 49%). 1H NMR (CDCl3): 1.58 (m, 4H), 1.97 (m, 3H), 3.91 (m, 3H), 4.15 (m, 1H), 4.40 (m, 1H), 6.85 (m, 1H), 6.98 (m, 1H), 7.48 (m, 1H), 7.56 (m, 1H), 7.72 (m, 1H), 7.99 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11](I)[N:10]=[N:9]1.[N:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[S:17][CH:16]=1.C([O-])(=O)C.[Na+]>CN(C=O)C.O>[N:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[S:17][C:16]=1[C:11]1[N:10]=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:12]=1[CH3:13]
Reactant: Cc1c(I)nnn1-c1ccccc1Cl
Reactant: c1cnc2scnc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2nc3cccnc3s2)nnn1-c1ccccc1Cl
Temperature: 140 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
Under nitrogen atmosphere, 344 mg of 1-(2-chlorophenyl)-4-iodo-5-methyl-[1,2,3]-triazole and 276 mg of thiazolo(5,4-b)pyridine (B. Stanovnik, Synthesis, 1974, 120) were dissolved in 3 ml of DMF. Then, 100 mg of sodium acetate and 103 mg of Herrman catalyst were added, and the mixture was stirred at 140° C. for 8 hours. After diluting the reaction solution with water, the resultant was extracted with chloroform. Organic layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The residues obtained by distilling out the solvents were separated and purified by thin-layer silicagel column chromatography (ethyl acete/hexane=1/1) to obtain 30 mg of the above compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[OH:25][CH:26]([P:28](=[O:33])([O:31][CH3:32])[O:29][CH3:30])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])=[CH:6][C:7]=1[O:25][CH:26]([P:28](=[O:33])([O:31][CH3:32])[O:29][CH3:30])[CH3:27])([O-:13])=[O:12]
Reactant: COP(=O)(OC)C(C)O
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COP(=O)(OC)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (600 mg), dimethyl α-hydroxyethylphosphonate (382 mg), potassium carbonate (343 mg) and 2-butanone (8 ml) is heated under reflux for 24 hours. The reaction mixture is filtered, and the filtrate is concentrated and purified by prep. TLC to give dimethyl α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphonate.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:12])[CH:5]([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][O:21]2)=[CH:16][CH:15]=1>>[CH3:12][C:4]([CH:5]([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][O:21]2)=[CH:16][CH:15]=1
Reactant: Oc1ccc2c(c1)OCCC2
Reactant: CC(C)=CCC(C)C(C)=CCBr
Product: CC(C)=CCC(C)C(C)=CCOc1ccc2c(c1)OCCC2

Procedure:
Following the procedure of Example 1, 1-bromo-3,4,7-trimethyl-2,6-octadiene and 7-hydroxy-chromane are reacted to form 7-(3,4,7-trimethyl-2,6-octadienyloxy)-chromane; nD20 = 1.5368.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:10][CH2:11][CH2:12][NH2:13]>>[C:2]1([NH:1][CH2:10][CH2:11][CH2:12][NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCBr
Reactant: Nc1ccccc1
Agent: Br
Product: NCCCNc1ccccc1

Procedure:
Prepared in the manner of Example 1, Step A from aniline and 3-bromopropylamine hydrobromide salt.
Reaction SMILES: [CH3:1][C:2]1([C:5]([NH2:7])=[O:6])[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:19]([O:21][C:22]([CH3:24])=[CH2:23])=[O:20]>C1COCC1>[CH3:1][C:2]1([C:5]([NH:7][C:19](=[O:20])[O:21][C:22]([CH3:24])=[CH2:23])=[O:6])[CH2:4][CH2:3]1
Reactant: CC1(C(N)=O)CC1
Reactant: C=C(C)OC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C1(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.2 %

Procedure:
A −78° C. solution of 1-methylcyclopropanecarboxamide (1.35 g, 13.62 mmol) in THF (30 mL) was treated drop-wise with lithium bis(trimethylsilyl)amide (1 M THF, 17.7 mL, 17.7 mmol), stirred for 0.5 h, treated drop-wise with a solution of isopropenyl chloroformate (1.94 mL, 17.7 mmol) in THF (5 mL), stirred at −78° C. for 1 h, then allowed to warm to RT and stirred for 1 h. The mixture was quenched with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford crude prop-1-en-2-yl (1-methylcyclopropanecarbonyl)carbamate (2.9 g, 116%) which was used without further purification.