Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[OH:18].[Br:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.[F-].[Cs+]>COCCOC.CO.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>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:7]2[CH:6]=[CH:5][C:4]([OH:18])=[C:3]([O:2][CH3:1])[CH:8]=2)=[CH:22][CH:21]=1
Reactant: Brc1ccc(Br)cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COc1cc(-c2ccc(Br)cc2)ccc1O
Temperature: 70 °C
Yield: 54.1 %

Procedure:
A mixture of 2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.250 g, 1.00 mmol), 1,4-dibromo benzene (0.259 g, 1.10 mmol), Pd(PPh3)4 (0.0580 g, 5%), and CsF (0.456 g, 3.00 mmol) in DME/MeOH (25 mL, 1:1) was heated at 70° C. overnight. The reaction mixture was concentrated and the residue was extracted with CH2Cl2, washed with water, dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with hexane/CH2Cl2 (1:9) to give 0.151 g (54%) of the desired product. MS (DCI/NH3) m/z: 279.9 (M+H)+; 1H NMR (300 MHz, CD3OD) δ 3.91 (s, 3H), 6.86 (d, J=8.14 Hz, 1H), 7.06 (m, 1H), 7.14 (d, J=2.03 Hz, 1H), 7.44-7.58 (m, 3H).
Reaction SMILES: [Mg].Br[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[CH:11]1[C:24]2[C:23](=O)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O1CCCC1.C1C=CC=CC=1>[CH:7]([C:6]1[CH:9]=[CH:10][C:3]([C:23]2[C:24]3[C:15]([N:16]=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:5]=1)=[CH2:8]
Reactant: C=Cc1ccc(Br)cc1
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Mg]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2c3ccccc3nc3ccccc23)cc1
Reaction time: 8 h
Yield: 42.1 %

Procedure:
Into a four-neck flask equipped with a stirrer, a nitrogen gas inlet tube, a reflux condenser with a calcium chloride tube and a dropping funnel were charged 4.9 g of magnesium cut powder and 50 ml of tetrahydrofuran. 36.6 Grams of p-bromostyrene diluted with tetrahydrofuran to about 4 times the weight was added dropwise under gentle reflux in a dry nitrogen gas stream. After the magnesium had disappeared, a solution consisting of 37.0 g of acridone and 600 ml of tetrahydrofuran was added dropwise over a period of two hours with stirring. After refluxing for further 5 hours, the reaction mixture was allowed to cool and then poured onto hydrochloric acid-ice to effect hydrolysis. The organic layer was extracted with ether and the extract was dried over anhydrous sodium sulfate. The solvent was then distilled off to obtain a yellow semi-solid. Almost the same weight (60 g) of phosphorus pentoxide was added to 500 ml of a solution of the semi-solid in benzene. The mixture was stirred at room temperature for 5 hours and then allowed to stand overnight. The supernatant liquid separated by decantation was washed with water, dried, and then concentrated to dryness. The residue was purified by silica gel chromatography to obtain 22.5 g of 9-(p-vinylphenyl)acridine. Yield 42.1%.
Reaction SMILES: [F:1][C:2](=[C:6]([F:8])[F:7])[CH2:3][CH2:4][OH:5].CC(C)=[O:11].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2](=[C:6]([F:8])[F:7])[CH2:3][C:4]([OH:11])=[O:5]
Reactant: CC(C)=O
Reactant: OCCC(F)=C(F)F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CC(F)=C(F)F

Procedure:
The first method involves hydrolysis of 4-bromo-1,1,2-trifluoro-1-butene (II) with water in the presence of N-methyl pyrrolidinone to give 3,4,4-trifiuoro-3-buten-1-ol (III), followed by Jones oxidation under conditions not previously known. These conditions are at a temperature of about 51°-54° C. In addition, the 3,4,4-trifluoro-3-buten-1-ol in acetone solvent and the Jones reagent are added to the reaction vessel simultaneously to afford 3,4,4-trifluoro-3-butenoic (IV) acid in 52% overall yield. ##STR4##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(N(CC)C(C)C)(C)C.[C:35]1([C:41]2[O:45][N:44]=[C:43]([NH:46][C:47](=O)[O:48]C3C=CC=CC=3)[CH:42]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([NH:22][C:47]([NH:46][C:43]2[CH:42]=[C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[O:45][N:44]=2)=[O:48])[CH:23]=[CH:24][CH:25]=1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(-c2ccccc2)on1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(-c5ccccc5)on4)c3)c2cc1OC
Temperature: 50 °C
Yield: 69.5 %

Procedure:
According to the procedure described in Example 113C, 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (102 mg, 0.3 mmol) in THF (1.5 mL) was treated with N,N-diisopropylethylamine (68 μl, 0.39 mmol), 4-(dimethylamino)pyridine (1.8 mg, 0.015 mmol) and phenyl 5-phenylisoxazol-3-ylcarbamate from Example 113B (109 mg, 0.39 mmol). The reaction mixture was heated to 50° C. for 4 h. After cooling to room temperature, the mixture was partitioned between chloroform and a saturated solution of sodium bicarbonate. The water phase was back extracted three times with chloroform and the organics combined and dried (MgSO4). Concentration under reduced pressure gave a residue which was purified by preparative HPLC (phenylhexyl reverse phase column). The obtained solid was triturated with anhydrous diethyl ether to afford 1-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)-3-(5-phenylisoxazol-3-yl)urea as a white solid (110 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.06 (s, 1H), 8.57 (s, 1H), 7.86 (d, 2H), 7.62-7.53 (m, 5H), 7.51 (t, 2H), 7.28 (m, 2H), 6.99 (d, 1H), 4.34 (bs, 2H), 4.00 (s, 3H), 3.77 (bs, 2H), 3.35 (s, 3H); LC-MS (ESI) m/z 528 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH3:37])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][Mg]Br.O>O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([OH:14])[CH3:38])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:36][CH3:37])[CH:18]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(COc2nn(Cc3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C(C)O)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.30 g) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (0.9 M tetrahydrofuran solution, 1.3 mL) at 0° C., and the mixture was stirred at the same temperature for 1 hr. Water was added to 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 to give 1-{1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}-1-ethanol as colorless crystals (0.27 g, yield 87%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 105-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cu][C:12]#[N:13].C(#N)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[C:12]#[N:13]
Reactant: N#C[Cu]
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CC#N
Product: N#CC(=O)c1ccccc1Cl
Temperature: 25 °C
Yield: 74.3 %

Procedure:
17.5 g (0.1 mol) 2-chlorobenzoyl chloride, 11.65 g (0.13 mol) copper (I) cyanide, and 8 mL of acetonitrile in 15 mL of toluene was refluxed for 3 hours, and then cooled to room temperature. Insoluble material was filtered and the residue was washed with toluene. The solvent in the resulting filtrate was evaporated under reduced pressure, and the residue was distilled to yield 12.3 g of 2-chlorophenyloxoacetonitrile (yield=75%).
Reaction SMILES: [F:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Li+]>CO.O>[F:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1c(OC)ccc(OC)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(OC)c(C(=O)O)c1F
Temperature: 80 °C
Yield: 98.2 %

Procedure:
To a mixture of ethyl 2-fluoro-3,6-dimethoxybenzoate (8.1 g, 35.5 mmol) in methanol (150 mL) and water (50 mL), lithium hydroxide (7.5 g, 178 mmol) was added. The resulting mixture was heated at 80° C. for 5 h. The reaction mixture was concentrated to remove methanol, acidified with 2 M HCl until pH 4, and extracted with dichloromethane (4×200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give the title compound (6.98 g). 1H NMR (DMSO-d6): δ 13.39 (br s, 1H), 7.19 (t, 1H), 6.82 (dd, 1H), 3.79 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:19]#[N:20])[CH2:4][CH3:5])[CH3:2].COC1C=CC(/C=[C:36]2/[C:37]([NH:39][C:40]([S:42]/2)=[NH:41])=[O:38])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:41][C:40]1[S:42]/[C:36](=[CH:17]\[C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][C:8]([C:19]#[N:20])=[C:7]3[O:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])/[C:37](=[O:38])[N:39]=1
Reactant: CCC(CC)Oc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(CC)Oc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 4-(1-ethyl-propoxy)-6-formyl-quinoline-3-carbonitrile (example 64b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(1-ethyl-propoxy)-quinoline-3-carbonitrile. LC-MS m/e 367 (MH+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[NH:13][C@H:12]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O)(C)(C)C.C1COCC1>Cl.C(Cl)Cl>[NH2:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[NH:13][C@H:12]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(=O)N[C@H]1Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)C[C@@H]1OC(=O)N[C@H]1Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
The crude, wet product of Example 3a was slurried in 1N HCl (192 mL) and the slurry was heated to 70° C. with stirring. After 1 hour, THF (100 mL) was added and stirring at 65° C. was continued for 4 hours. The mixture was then allowed to cool to 20-25° C. and was stirred overnight at 20-25° C. The THF was removed by evaporation under vacuum and the resulting aqueous solution was cooled to about 5° C., causing some precipitation to occur. The aqueous mixture was adjusted to pH 7 by addition of 50% aqueous sodium hydroxide (about 18.3 g). The resulting mixture was extracted with ethyl acetate (2×100 mL) at about 15° C. The combined organic extracts were washed with 100 mL of brine and the organic layer was separated and stirred with sodium sulfate (5 g) and Darco G-60 (3 g). This mixture was warmed on a hot plate for 1 hour at 45° C. The hot mixture was then filtered through a bed of diatomaceous earth and the filter pad was washed with ethyl acetate (100 mL). The filtrate was evaporated under vacuum to provide an oil. The oil was redissolved in methylene chloride (300 mL) and the solvent was evaporated under vacuum. The resulting oil was dried at room temperature under vacuum to provide the desired product (18.4 g) as a glassy syrup.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH:25]=[CH:26][CH:27]=O>C1COCC1>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[CH:25]=[CH:26][CH:27]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=CC=Cc1c(F)cccc1F
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=CC=Cc1c(F)cccc1F
Reaction time: 3 h

Procedure:
Ethyl (diethoxy-phosphoryl)-acetate (3.72 ml, 18.7 mmol) in solution in THF (114 ml) is treated with sodium hydride (60% in oil) (819 mg, 20.4 mmol) at room temperature for 5 minutes. 3-(2,6-Difluoro-phenyl)-propenal (2.87 g, 17.0 mmol) in solution in THF (29 ml) is then added dropwise. After 3 hours of agitation at room temperature, the mixture is evaporated to dryness, taken up in ethyl acetate and washed with water. The organic phase is dried on Na2SO4, filtered and evaporated to dryness. The yellow solid obtained is used directly in the following reaction.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[CH:7]=[C:8]([S:13][Si](C)(C)C)[CH:9]=[CH:10][C:11]=1[Cl:12]>C(#N)C.CN(C)P(=O)(N(C)C)N(C)C>[Cl:5][C:6]1[CH:7]=[C:8]([S:13][CH2:2][C:3]#[N:4])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: C[Si](C)(C)Sc1ccc(Cl)c(Cl)c1
Reactant: N#CCCl
Solvent: CC#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CCSc1ccc(Cl)c(Cl)c1
Reaction time: 0.03 h
Yield: 96.9 %

Procedure:
3.5 ml (55 mmoles) of chloroacetonitrile were added to a refluxing solution of 11.0 g (44 mmoles) of 3,4-dichlorophenylthio(trimethyl)silane in a mixture of 25 ml of acetonitrile and 10 ml of hexamethylphosphoric triamide and the reaction was complete with 2 minutes. The residue obtained after evaporation of the acetonitrile was dissolved in ethyl acetate, and the solution was washed with water, dried and evaporated to dryness to obtain 9.30 g (93% yield) of (3,4-dichlorophenylthio)acetonitrile boiling at 127°-130° C./0.4 mm Hg and having a refractive index of nD25 =1.5920.
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[OH:22]S(O)(=O)=O>>[CH3:12][O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:13])[CH:3]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]2=[O:22]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C2=C(N)c3cc(OC)ccc3C2=O)cc1
Product: COc1ccc(C2C(=O)c3ccc(OC)cc3C2=O)cc1
Yield: 99 %

Procedure:
3-Amino-5-methoxy-2-(4-methoxyphenyl)-1H-inden-1-one (500 mg, 1.78 mmol), was suspended in a solution of 20% H2SO4 and heated to 120° for 1 h. The reaction was allowed to cool and the residual solid filtered and the filter cake was washed copiously with water and dried in vacuo to give a light white solid (0.5 g, 99% yield, m.p. 163° C.);
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:4]=[CH:5][N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.[Li]CCCC.CN([CH:26]=[O:27])C>>[F:17][C:2]([F:16])([F:1])[C:3]1[N:4]=[C:5]([CH:26]=[O:27])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[CH:7]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1cnc(C(F)(F)F)c1
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1C=O
Yield: 14.2 %

Procedure:
Reaction of 4-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (590 mg, 2.2 mmol), 2.3 M n-BuLi (1.3 mL, 3.0 mmol), and DMF (0.51 mL, 6.6 mmol) followed by purification of the crude material on silica gel (10% EtOAc/hexanes) gave the title compound as a yellow oil (92 mg, 14% over two steps). 1H NMR (CDCl3) □0.02 (s, 9H), 0.95 (m, 2H), 3.60 (m, 2H), 5.79 (s, 2H), 7.28 (s, 1H), 7.67 (s, 1H), 9.86 (s, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].B(F)(F)F.CCOCC.[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-]>CCOCC.C([O-])([O-])=O.[Na+].[Na+].O>[CH2:30]([O:29][C:27]([CH:26]1[C:11](=[O:14])[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH2:13][CH2:12]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
To a 0° C. solution of 1-BOC-4-piperidone (20 g, 0.10 mol) in Et2O (200 mL) was added BF3.Et2O (14 mL, 0.11 mol) followed by drop-wise addition of ethyl diazoacetate (13.7 mL, 0.11 mol) over 1 h. After addition was complete, the mixture was stirred at 0° C. for 1 h. The mixture was diluted with 30% aq. Na2CO3 and water at 0° C. and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. Purification of the residue (FCC) afforded the title compound (25.6 g, 98%). 1H NMR (CDCl3): 4.25-2.03 (m, 11H), 1.47-1.45 (d, J=7.8 Hz, 9H), 1.31-1.24 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:24]3[CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22][CH2:23]3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)NC(=O)c1cccc3c1N2CC3
Reactant: CC1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)N=C(N1CCC(C)CC1)c1cccc3c1N2CC3
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 6.26 g (0.0250 mole) of 9-methyl-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1000 ml of toluene was heated under nitrogen until a solution resulted. Then there was added 24.8 g (0.250 mole) of 4-methylpiperidine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for three hours, cooled to room temperature and filtered. The filtrate was stirred with 500 ml of 2N sodium hydroxide solution for 15 minutes and the layers were separated. The aqueous phase was extracted with 250 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to 8.1 g (98%) of product. Recrystallization from ethyl acetate provided the analytical sample, mp 194°-196° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[Ca+2].Br.[Br:19][CH2:20][CH2:21][NH:22]C1C=CC=CC=1>O>[OH2:11].[BrH:19].[CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH:4][CH2:20][CH2:21][NH2:22]
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1N
Reactant: BrCCNc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: Cc1cc(N)c([N+](=O)[O-])cc1NCCN
Temperature: 0 °C

Procedure:
A suspension of 0.05 mol (8.35 g) of 2-methyl-4-amino-5-nitroaniline and 0.035 mol (3.5 g) of calcium carbonate in 100 ml of water is heated beforehand on a boiling water-bath, whilst stirring. A solution of 0.07 mol (14.35 g) of β-bromoethylaniline hydrobromide in 20 ml of water is added gradually, whilst stirring. After heating for two hours on the boiling water-bath, the hot reaction medium is filtered. After cooling the filtrate for 24 hours at 0° C., the expected product, which has crystallised in the form of the hydrobromide, is filtered off. The crude product is washed with acetone and then recrystallised from boiling water. After filtration, washing with acetone and drying in vacuo, 2-methyl-4-amino-5-nitro-N-(β-aminoethyl)-aniline hydrobromide monohydrate is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=O)[C:5](=[O:12])[N:6]2[CH3:11].O.NN>ClCCl.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:12])[N:6]2[CH3:11]
Reactant: CN1C(=O)C(=O)c2c(Cl)cccc21
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)Cc2c(Cl)cccc21
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-chloroisatin (CAS#6344-05-4, 3.64 g, 20.0 mmol) in acetonitrile (150 mL) was added potassium carbonate (11.1 g, 80 mmol) followed by iodomethane (2.75 mL, 44.0 mmol). The reaction was then placed at 60° C. and stirred for 40 minutes. The reaction was then cooled to room temperature, filtered and concentrated to 10% of the original volume. The reaction was then diluted with dichloromethane, water, and brine. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate filtered, and concentrated to provide 4-chloro-1-methyl-1H-indole-2,3-dione as an orange solid without the need for further purification. The 4-chloro-1-methyl-1H-indole-2,3-dione (1.55 g, 7.92 mmol) was then treated with hydrazine hydrate (14.8 ml, 475 mmol). The reaction was then placed at 70° C. and heated to 130° C. over 20 minutes. The reaction was stirred at 130° C. for 45 minutes, at which time the reaction was placed at room temperature and cooled by the addition of ice. Once the reaction was cooled to room temperature it was diluted with dichloromethane and water and the layers were then separated. The aqueous layer was extracted an additional two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane 0 to 2%) to afford 4-chloro-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 182.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:22].[OH-].[K+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)=[O:22])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1ccc(S(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A mixture of 4-(4-chlorophenylthio)benzaldehyde (3.63 mmol, 900 mg), 3-chloroperoxybenzoic acid (max 77%, 3.63 mmol, 813 mg) and CH2Cl2 (5.00 mL), was stirred at room temperature for 60 min and poured into a separatory funnel with 5% aqueous KOH solution (10 mL). The phases were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were washed with water (10 mL), brine (50 mL) and dried over MgSO4. Removal of solvents in vacuo gave a light yellow liquid. Purification by flash column chromatography (eluent: 5% EtOAc in Hexane) provided 4-[(4-chlorophenyl)sulfinyl]benzaldehyde (500 mg, 52.2% yield) as a light yellow solid. 1H NMR (CDCl3) δ 10.04 (s, 1H), 7.98 (d, J=8.2 Hz, 2H), 7.82 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H).