Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=2)[CH:3]=1.[CH3:24][C@@H:25]1[CH2:30][NH:29][CH2:28][CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:29]3[CH2:28][CH2:27][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:25]([CH3:24])[CH2:30]3)[N:7]=[C:6]3[CH2:8][CH2:9][CH2:10][C:5]=23)=[CH:13][CH:14]=1)[CH3:23]
Reactant: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc3c2CCC3)cc1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Product: CCOC(=O)Cc1ccc(Nc2cc(N3CCN(C(=O)OC(C)(C)C)[C@H](C)C3)nc3c2CCC3)cc1
Yield: 27.4 %

Procedure:
Following general procedure B1, ethyl 2-(4-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.094 g, 0.28 mmol) was reacted with (R)-tert-butyl 2-methylpiperazine-1-carboxylate (0.112 g, 0.56 mmol) to afford the title compound (0.038 g, 27%) as an orange foam. MW=494.63. 1H NMR (CDCl3, 500 MHz) δ 7.26 (d, J=8.3 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 6.14 (s, 1H), 5.58 (s, 1H), 4.27 (br s, 1H), 4.17 (q, J=7.0 Hz, 2H), 4.04-3.97 (m, 1H), 3.91-3.84 (m, 1H), 3.79-3.73 (m, 1H), 3.60 (s, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.86-2.78 (m, 1H), 2.70 (t, J=7.5 Hz, 2H), 2.11 (quin, J=7.5 Hz, 2H), 1.47 (s, 9H), 1.27 (t, J=7.0 Hz, 3H), 1.20 (d, J=6.6 Hz, 3H); APCI MS m/z 495 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH:9]([OH:15])(O)[C:10]([F:13])([F:12])[F:11]>>[F:11][C:10]([F:13])([F:12])[CH:9]([C:1]1[CH:2]=[C:3]([CH3:8])[CH:4]=[C:5]([CH:9]([OH:15])[C:10]([F:13])([F:12])[F:11])[C:6]=1[OH:7])[OH:15]
Reactant: OC(O)C(F)(F)F
Reactant: Cc1ccc(O)cc1
Product: Cc1cc(C(O)C(F)(F)F)c(O)c(C(O)C(F)(F)F)c1
Temperature: 105 °C

Procedure:
5.8 g (50 mmol) of p-cresol and 15.5 g (100 mmol) of 75% fluoral hydrate are introduced into a 100 ml reactor. 5 g of MgO are added. The mixture is heated at 105° C. for 8 hours. After treating according to the protocol described in Example 1, 70% of dihydroxyalkylated product are obtained.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:4].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][NH2:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[Cl:12][C:8]1[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:24][CH2:23][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CBr)Nc1cccc(Cl)c1
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(CNCC(=O)Nc2cccc(Cl)c2)cc1OC

Procedure:
In a manner similar to Preparation 11, react 2-bromo-N-(3-chlorophenyl)acetamide (4.4 g, 18 mmol) with 3,4-dimethoxybenzenemethanamine (8.7 g, 53 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[CH:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])[CH3:3].[ClH:24].[O:25]([NH2:27])[CH3:26].N1C(C)=CC=CC=1C>C1COCC1>[ClH:24].[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:8]([NH:27][O:25][CH3:26])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(C(Br)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: CON
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CONC(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 24 h

Procedure:
Over a 20 minute period a solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-α-phenylbenzyl bromide, Example 17, (6.23 g, 0.0166 mole) in 100 mL THF is added to a mixture of methoxylamine hydrochloride (4.18 g, 0.05 mole) and 5.62 g (0.0524 mole) of 2,6 lutidine in 175 mL THF. The reaction mixture is heated under reflux for 16 hours. An additional 5.62 g (0.0524 mole) of 2,6 lutidine and 2.0 g (0.0239 mole) of methoxylamine hydrochloride is added and reflux is continued for 24 hours. The mixture is evaporated to dryness and the residue is taken up in Et2O, washed with H2O, 1N HCl, saturated NaHCO3 and brine. After evaporation to dryness the residue is treated with 5 mL of 20% ethereal HCl (w/v). Creamy white crystals form and are filtered off and recrystallized from EtOAc-Et2O to give an off-white solid, 3.6 g (57 %), m.p. 183°-185° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:10]1[CH:14]2[CH:15]3C=CC([CH:13]2C=[CH:11]1)C3>C1(C)C=CC=CC=1>[C:6]([O:5][C:1]([CH:2]1[CH2:13][CH:14]2[CH2:15][CH:3]1[CH:11]=[CH:10]2)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C1=CC2C3C=CC(C3)C2C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1CC2C=CC1C2
Reaction time: 5 h
Yield: 64.4 %

Procedure:
Into an autoclave with an internal volume of 2 liters, 256.3 g of t-butyl acrylate, 264.4 g of dicyclopentadiene and 1,040 g of toluene were charged, and the reaction was carried out at a temperature of 170° C. or higher for 5 hours. Subsequently, the reaction product was drawn out, and the toluene was evaporated, followed by distillation using a distillation column at 8.0 Torr and 87° C. to obtain 250 g of 5-t-butoxycarbonylbicyclo[2.2.1]hept-2-ene with a purity of 99.9% by weight. Using the same distillation column, the product was distilled at 0.07 Torr and 97 to 102° C. to obtain 100 g of 8-t-butoxycarbonyltetracyclo[4.4.0.12,5.17,10]dodec-3-ene with a purity of 99.9% by weight:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6](Br)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1cccnc1
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: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccnc4)cc23)CC1
Yield: 32.6 %

Procedure:
Following the general procedure of Example 65, a mixture of 1,1-dimethylethyl 4-[7-(aminocarbonyl)-5-bromo-1H-indazol-3-yl]-1-piperidinecarboxylate (Intermediate 5) (100 mg, 0.24 mmols), 3-pyridinylboronic acid (88.5 mg, 0.72 mmols), potassium carbonate (197 mg), and Pd(PPh3)4 (28 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (33 mg, 38%)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>O>[N:10]1[CH:11]=[CH:12][CH:13]=[N:14][C:9]=1[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: Clc1ncccn1
Reactant: O=Cc1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=Cc1cccn1-c1ncccn1
Temperature: 130 °C
Reaction time: 13 h
Yield: 27.2 %

Procedure:
A mixture of 1.9 g of 2-pyrrolecarbaldehyde, 2.3 g of 2-chloropyrimidine, 7.8 g of cesium carbonate and 20 ml of N-methylpyrrolidone was stirred at 130° C. for 13 hours, and then allowed to cool to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.94 g of 1-(2-pyrimidinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][CH2:64][N:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]2)[CH2:58][CH2:57]1>CC(N(C)C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][CH2:64][N:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]2)[CH2:58][CH2:57]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: C1CCN(CCOC2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OCCN2CCCCC2)CC1
Reaction time: 2 h
Yield: 20.9 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1)(0.20 g, 0.67 mmol) and HBTU (0.381 g, 1.01 mmol) were added to DMA (4 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 1-(2-(piperidin-4-yloxy)ethyl)piperidine (115) (0.214 g, 1.01 mmol). The reaction was stirred for 2 hours before being evaporated to dryness and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.069 g, 20.74% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.36-1.45 (2H, m), 1.64-1.94 (8H, m), 2.37-2.50 (4H, m), 2.55 (2H, t), 3.03-3.15 (1H, m), 3.37-3.49 (1H, m), 3.50-3.65 (4H, m), 3.92-4.04 (1H, m), 4.30 (2H, s), 7.00 (1H, t), 7.21-7.32 (2H, m), 7.68-7.79 (3H, m), 8.43-8.49 (1H, m), 10.49 (1H, s); m/z (LC-MS, ESI+), RT=2.01 (M+H 493.5).
Reaction SMILES: [C:1](O)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[NH:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl.CN(C)C=O>[C:1]([C:27]1[CH:26]=[C:25]([C:29]([O:31][CH3:32])=[O:30])[NH:24][CH:28]=1)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: COC(=O)c1ccc[nH]1
Reactant: CCCCCCCCCCCCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCC(=O)c1c[nH]c(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
In 480 ml of methylene chloride, were dissolved 102.9 g (0.48 mol) of tridecanoic acid, to which 52.6 ml (0.72 mol) of thionyl chloride and 0.2 ml of N,N-dimethylformamide were added to obtain a solution. The solution was allowed to stand over night and was evaporated under a reduced pressure. The remaining oil was added to 400 ml of methylene chloride containing 106.6 g (0.8 mol) of anhydrous aluminum chloride, to which 200 ml of methylene chloride solution containing 50.05 g (0.4 mol) of methyl pyrrole-2-carboxylate was added dropwise in 40 minutes at a temperature of 3° to 9° C. After the addition, the temperature of the mixture was elevated slowly up to room temperature and the mixture was stirred for 2 hours. Then, the mixture was poured into 800 ml of ice-water, and 1000 ml of methylene chloride was added thereto to dissolve all the crystals precipitated, followed by liquid separation. The organic layer was washed with water three times, dried over anhydrous magnesium sulfate and condensed under a reduced pressure. The residue was recrystallized from 400 ml of ethyl acetate and 400 ml of hexane to obtain 107.2 g of methyl 4-tridecanoylpyrrole-2-carboxylate as white crystals. The yield was 83% and the melting point was 92° to 93° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li].C[Si](N[Si](C)(C)C)(C)C.[C:28]1(=[O:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.O>O1CCCC1>[C:16]([CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[C:28]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)#[N:17]
Reactant: O=C1CCCCC1
Reactant: N#CCc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(c1ccc(OCc2ccccc2)cc1)C1(O)CCCCC1
Temperature: -78 °C
Yield: 69.5 %

Procedure:
p-Benzyloxyphenyl acetonitrile (50 g) was added to dry tetrahydrofuran (250 ml) and cooled to −78° C. Lithium HMDS (20.8 g) in tetrahydrofuran (60 ml) was added slowly to the reaction mixture at −70° C. followed by dropwise addition of cyclohexanone (26.6 g. 0.27 mol) and maintaining the temperature at −60° C. for 2 h. The reaction temperature was allowed to rise to 0° C., charged with water (300 ml) and the organic layer was separated. The aqueous layer was then extracted with ethylacetate. The two organic layers were combined, washed with DM water and dried using Na2SO4. The solvent was evaporated under reduced pressure to give 50 g (70.0%) of 1-[cyano(p-benzyloxyphenyl)methyl]-cyclohexanol.
Reaction SMILES: O[C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13].CCN(C(C)C)C(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Cl:38][C:39]1[CH:40]=[C:41]([C@H:46]2[CH2:50][CH2:49][NH:48][CH2:47]2)[CH:42]=[C:43]([Cl:45])[CH:44]=1>C(Cl)Cl.O>[Cl:38][C:39]1[CH:40]=[C:41]([C@H:46]2[CH2:50][CH2:49][N:48]([C@H:2]3[CH2:6][CH2:5][N:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:3]3=[O:13])[CH2:47]2)[CH:42]=[C:43]([Cl:45])[CH:44]=1
Reactant: Clc1cc(Cl)cc([C@H]2CCNC2)c1
Reactant: O=C1[C@H](O)CCN1c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccccc1
Reaction time: 0.33 h

Procedure:
Synthesized according to General Procedure 10. To a solution of (R)-3-hydroxy-1-phenylpyrrolidin-2-one (822 mg, 4.64 mmol) and DIEA (1.50 g, 2.02 mL, 11.59 mmol) in DCM (10 mL) at −20° C. was added triflic anhydride (1.57 g, 936 μL, 5.56 mmol) and the reaction mixture was stirred at this temperature for 20 min. A solution of (R)-3-(3,5-dichlorophenyl)pyrrolidine (835 mg, 3.86 mmol) in DCM (6 mL) was added and the reaction mixture was stirred at −20° C. for 1 hour. The reaction mixture was poured into water and extracted with EtOAc (3×). The combined organic extracts were washed with water (2×), brine, dried (Na2SO4) and evaporated to dryness. Purification by silica gel chromatography (30-60% EtOAc in hexane) gave (3R,3′S)-3-(3,5-dichlorophenyl)-1′-phenyl-1,3′-bipyrrolidin-2′-one as an oil that solidified upon standing (0.9 g, 62%). 1H-NMR (400 MHz, DMSO-d6) δ 7.67 (d, J=8.0 Hz, 2H), 7.42-7.36 (m, 5H), 7.15 (t, J=7.3 Hz, 1H), 3.77 (m, 2H), 3.52 (t, J=8.7 Hz, 1H), 3.05-2.98 (m, 4H), 2.88 (m, 1H), 2.31-2.23 (m, 2H), 2.06 (m, 1H) and 1.77-1.74 (m, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=375.5; tR=1.35 min.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][C:8]([CH3:10])=[O:9]>>[CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:1][C:2]1[O:6][C:8]([CH3:10])([CH3:7])[O:9][C:4](=[O:5])[CH:3]=1
Reactant: CC(C)=O
Agent: C=C1CC(=O)O1
Product: CC1=CC(=O)OC(C)(C)O1

Procedure:
Carroll and Bader (M. F. Carroll and A. R. Bader, J. Am. Chem. Soc., Vol. 75, 5400-5402(1953)) disclose the acidcatalyzed reactions of diketene with ketones which yielded 2,2-disubstituted-4-methyl-6-keto-1,3-dioxenes, many reactions of which dioxenes paralleled those of diketene. The adduct of diketene with acetone yielded 2,2,6-trimethyl-1,3-dioxen-4-one (TKD); the reactions of TKD with methanol or 1-butanol to yield methyl acetoacetate or n-butyl acetoacetate are exemplified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.O=[S:19](Cl)Cl>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[C:4]([CH:3]=1)=[N:10][S:19][N:9]=2
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1cc2nsnc2cc1Cl
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a solution of 4,5-dichlorobenzene-1,2-diamine (3.0 g, 0.017 mol) and triethylamine (9.45 mL, 0.068 mol) in dichloromethane (120 mL) was added SOCl2 (4.92 mL, 0.068 mol) dropwise at room temperature. The resulting reaction mixture was heated to reflux for 20 h. The reaction mixture was then allowed to cool to room temperature, and quenched with water carefully. The resulting mixture was extracted with dichloromethane, dried over Na2SO4 and concentrated on a rotary evaporator to give a dark solid as the crude compound. The crude compound was purified by flash column chromatography (silica gel, CHCl3) to afford 5,6-dichlorobenzo[1,2,5]thiadiazole as an off-white crystalline solid (2.35 g, 68% yield). 1H NMR (CDCl3 500 MHz): δ: 8.19 (t, 2H, J=8.5 Hz). 13C NMR (CDCl3, 500 MHz): δ 153.07, 135.28, 121.51. Anal. calcd. for (C6H2Cl2N2S): C, 35.14; H, 0.98; N, 13.66. Found: C, 35.08; H, 1.01; H, 13.56. m.p: 108-110° C.
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([N:11]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]1[C:20]1[O:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:32]([CH:34]1[O:36][CH2:35]1)Cl>O1CCOCC1>[O:36]1[CH2:35][CH:34]1[CH2:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[O:21][C:20]([C:12]3[N:11]([CH2:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=3)=[CH:24][CH:23]=2)=[CH:30][CH:29]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3Cc3ccccc3)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1cn(Cc2ccccc2)c(-c2ccc(-c3ccc(OCC4CO4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 48.1 ml of 1N sodium hydroxide solution and 18.5 ml of water is added to a solution of 18.5 g of 2-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-5-(4-hydroxyphenyl)-furan in 160 ml of dioxan and the mixture is stirred for 10 minutes at room temperature. After the addition of 13.3 g of epichlorohydrin, the mixture is stirred for a further 48 hours at room temperature, then filtered and the filter residue is washed with dioxan/water 1:1 and then with ether. After drying, 2-[4-(2,3-epoxypropoxy)-phenyl]-5-[1-benzyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-furan is obtained in the form of a white crystallisate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][CH:9]([CH2:15][Br:16])[C:10]([N:12]=[C:13]=[O:14])=[O:11]>C1C=CC=CC=1>[C:2]1([NH:1][C:13]([NH:12][C:10](=[O:11])[CH:9]([Br:8])[CH2:15][Br:16])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C=NC(=O)C(Br)CBr
Solvent: c1ccccc1
Product: O=C(NC(=O)C(Br)CBr)Nc1ccccc1
Temperature: 12.5 °C
Reaction time: 2 h

Procedure:
9.5 g of aniline are dissolved in 100 ml of anhydrous benzene and a solution of 26.0 g of 2,3-dibromopropionyl isocyanate in 100 ml of benzene is added dropwise with cooling at 10 to 15° C. After stirring for 2 hours, the crystal sludge is diluted with the same volume of petroleum ether, filtered, washed with petroleum ether and dried. Yield: 30.0 g, m.p: 160°-161° C.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:26][OH:27]>O>[OH:27][N:26]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8]1
Reactant: NO
Reactant: O=C1CC(c2ccccc2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: ON=C1CC(c2ccccc2)c2ccccc21
Temperature: 0 °C

Procedure:
A mixture of 3-phenylindan-1-one (80 g), methanol (935 ml), water (90 ml), potassium carbonate (103.8 g), and hydroxylamine HCl (104.3 g) was heated at reflux for 16 hours, then poured into ice-water: the title compound was filtered, washed with water, with a small portion of ether, then dried in air. Yield: 74.7 g; m.p. 133°-139°.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3](=N)[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.OCC[CH2:18][C:19](=[O:21])[CH3:20].FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:5]([O:4][CH2:3][CH2:2][CH2:18][C:19](=[O:21])[CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)CCCO
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)CCCOCc1ccccc1
Reaction time: 8 h
Yield: 64.9 %

Procedure:
Benzyl trichloroacetimidate (1.85 g) was added to a mixed solution of 5-hydroxy-2-pentanone (500 mg, 4.89 mmol) in dichloromethane (20 mL) in an argon atmosphere at room temperature, and then trifluoromethanesulfonic acid (87 μL) was added in an ice bath. The mixture was returned to room temperature and stirred overnight. After completion of the reaction, a saturated sodium bicarbonate solution was added to the reaction solution in an ace bath, and the pH was adjusted to 8. After extraction with chloroform-water, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 610 mg of the title compound (yield: 65%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([OH:11])=[C:5]2[CH:4]=1)[CH3:2].[N+:18]([O-])([O-:20])=[O:19].[Na+]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[S:17][C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([OH:11])=[C:5]2[C:4]=1[N+:18]([O-:20])=[O:19])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1cnc2sc(CC)cc2c1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cnc2sc(CC)c([N+](=O)[O-])c2c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of ethyl 2-ethyl-4-hydroxythieno[2,3-b]pyridine-5-carboxylate (1.0 g, 4.0 mmol) in conc. sulfuric acid (10 ml) was cooled to -5° C. and a solution of sodium nitrate (370 mg, 4.3 mmol) in conc. sulfuric acid (5 ml) was added dropwise to the chilled solution. The reaction mixture was stirred at -3° C. to -5° C. for 1 hour and poured into ice-water. The precipitated product was collected by filtration and washed with cold water and then ethanol. The resulting precipitate was dissolved in chloroform, washed with a saturated aqueous sodium chloride, dried (MgSO4) and evaporated in vacuo. The resulting yellow solid was washed with a mixture of ether/hexane, and dried to give 960 mg (81%) of the title compound.