Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]2C(CC(O)C)=CC=C3C([NH:18][C:19](=O)[C:14]=23)=O)[CH2:9][CH2:8]1.NN.C[OH:31]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]([OH:31])[CH2:19][NH2:18])[CH2:9][CH2:8]1
Reactant: CO
Reactant: CC(O)Cc1ccc2c(c1N1CCC(c3ccccn3)CC1)C(=O)NC2=O
Agent: NN
Product: NCC(O)CN1CCC(c2ccccn2)CC1
Yield: 98 %

Procedure:
A mixture of 3-[4-(2-pyridyl)- piperidin-1-yl](2-hydroxypropyl)phthalimide (1.35 g, 3.68 mmol) and hydrazine (0.588 g, 18.4 mmol) in methanol (15 mL) was stirred and refluxed for 4.5 h. It was cooled, filtered, and the solid was washed with methanol (30 mL). Evaporation of solvent from the filtrate gave the product as a viscous oil (0.85 g, 98%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:21]=1.[CH3:22][O:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[OH:39].[F-].[Cs+]>COCCOC.CO>[OH:39][C:25]1[CH:26]=[CH:27][C:28]([C:2]2[CH:3]=[CH:4][C:5]3[C:11](=[O:12])[NH:10][C:9]4[CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=[CH:16][C:8]=4[NH:7][C:6]=3[CH:21]=2)=[CH:29][C:24]=1[O:23][CH3:22]
Reactant: COC(=O)c1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)c1ccc2c(c1)NC(=O)c1ccc(-c3ccc(O)c(OC)c3)cc1N2
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A mixture of Example 1B (92 mg, 0.3 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (112 mg, 0.45 mmol), Pd(PCy3)2Cl2 (11 mg, 0.015 mmol), and CsF (144 mg, 0.9 mmol) in DME (20 mL) and methanol (10 mL) was heated to reflux for 16 hours, cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide 95 mg (81%) of the desired product. MS (DCI) m/e 391 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.26 (s, 1H), 8.36 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.60 (d, J=2.2 Hz, 1H), 7.55 (dd, J=8.1, 1.9 Hz, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.17-7.19 (m, 2H), 7.06-7.09 (m, 2H), 6.87 (d, J=8.1 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: C(O[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[CH:6]=1)C.[C:13](OC(C)(C)C)(=O)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].S(=O)(=O)(O)O>CCCCCCC.O>[CH3:11][C:7]1[CH:6]=[C:5]([C:4](=[O:12])[CH3:13])[CH:10]=[CH:9][N:8]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1ccnc(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: O
Solvent: CCCCCCC
Product: CC(=O)c1ccnc(C)c1
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-isonicotinic acid ethyl ester (3.20 g) and tert-butyl acetate in n-heptane at −5° C. was slowly added lithium hexamethyldisilazide (46.5 mL; 1 M solution in THF). After stirring for 2 h, a solution of sulfuric acid (4.13 mL) in water (20 mL) was added within 20 min keeping the reaction temperature below 10° C. After the addition was completed, the reaction mixture was heated to reflux overnight. Extraction over a sat. solution of NaHCO3 (100 mL) with ethyl acetate (3×50 mL) and drying of the combined organic phases over Na2SO4 provided after evaporation of the organic solvent the title compound as a light brown liquid (2.40 g, 92%), which was used for the consecutive step without any further purification, MS (ESI+): m/z=136.0 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([CH3:16])([CH3:15])[C:8](=[O:14])[NH:9]2)C=C.CN(C)[C:19]1[CH:24]=CC=C[CH:20]=1>>[CH2:24]([C:13]1[C:5]([OH:4])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:14])[C:7]2([CH3:15])[CH3:16])[CH:19]=[CH2:20]
Reactant: C=CCOc1cccc2c1C(C)(C)C(=O)N2
Reactant: CN(C)c1ccccc1
Product: C=CCc1ccc2c(c1O)C(C)(C)C(=O)N2
Temperature: 205 °C

Procedure:
914 mg (4.21 mmol) of 4-allyloxy-2,3-dihydro-3,3-dimethyl-1H-indol-2-one was added to 4 ml of N,N-dimethylaniline, and the mixture was heated for 30 hours at 205° C. while stirring. After the reaction, N,N-dimethylaniline was evaporated under reduced pressure. The residue was dissolved in chloroform, washed with water, 2N hydrochloric acid, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, chloroform:ethyl acetate=20:1), washed with ether-n-hexane, and filtered to obtain 890 mg (yield: 97.4%) of a brown oil of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N:30]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[C:31]=[O:32]>O1CCCC1>[CH2:33]([NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 1.69 mmol) in tetrahydrofuran (5 mL) and triethyl-amine (0.47 mL, 3.38 mmol) was added isocyanatomethyl-benzene (0.25 mL, 2.03 mmol) dropwise. The reaction mixture was stirred at 25° C. for 3 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(3-benzyl-ureido)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (215 mg, 29%) as a white solid: LC/MS m/e calcd for C26H27N3O3 (M+H)+: 430.52, observed: 430.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:30])[CH2:26][CH2:27][C:28]#[CH:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([C:29]#[C:28][CH2:27][CH2:26][CH2:25][OH:30])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(F)cc3)csc2c1)C(F)(F)F
Reactant: C#CCCCO
Product: OCCCC#Cc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-fluoro-phenyl)-benzo[b]thiophene-6-yl ester and 4-pentyn-1-ol were converted to yield 5-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yl]-pent-4-yn-1-ol as light green solid, MS: 310 (M).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>CN(C=O)C.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C:26]([CH3:32])([CH3:31])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(N)CC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CC(=O)O)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Yield: 41 %

Procedure:
To mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 3-amino-3-methyl-butyric acid ((97 mg, 0.94 mmol) (Oakwood) in DMF (3 mL) was added NaOMe solid (68 mg, 1.25 mmol). The resultant mixture was heated in a 150-160° C. oil bath for 3 h. Reaction mixture was diluted with water (100 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected and dried. Crude residue was purified by silica gel chromatography, eluting with 10-50% EtOAc/CH2Cl2. Fractions containing the produce were collected and concentrated. It was triturated with MeOH (2 mL). Solid was collected and dried in vacuo to provide the title compound 51 mg (0.13 mmol) in 41% yield. LC-MS ESI−: 404.06 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]([C:31]2[CH:41]=[C:40]([CH3:42])[C:34]3[N:35]([CH3:39])[C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:39][N:35]1[C:34]2[C:40]([CH3:42])=[CH:41][C:31]([C:29]([C:24]3[N:25]=[C:26]([CH3:28])[N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[O:30])=[CH:32][C:33]=2[O:37][C:36]1=[O:38]
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)n1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)nc(C)n3)CC1)C(=O)N2

Procedure:
83 mg (0.30 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 95 mg (0.30 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.11 mL (0.60 mmol) DIPEA were stirred overnight in 3 mL DMF at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down i. vac. The residue was neutralised with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][Cl:42]>CN(C=O)C.C(OCC)(=O)C>[Cl:42][CH2:41][CH2:40][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=4[CH3:12])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:32])[CH:14]=3)[C:19]2=[O:23])=[CH:30][CH:29]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(O)cc3)ccc2c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(OCCCl)cc3)ccc2c1
Temperature: 50 °C
Reaction time: 40 h

Procedure:
To a solution of the product of step i) (500 mg) in DMF (10 mL) was added potassium carbonate (820 mg) and 1-bromo-2-chloroethane (0.2 mL) and the reaction was heated at 50° C. for 22 hours. Additional 1-bromo-2-chloroethane (0.3 mL) and potassium carbonate (820 mg) were added and heating continued for 40 hours. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and brine, dried over magnesium sulphate and evaporated. The residue was purified (SiO2, ethyl acetate:isohexane (6:4)) to yield the sub-titled compound (280 mg).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][C:13]([CH2:14][CH:15]([CH3:17])[NH2:16])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:29][CH2:30][Cl:31])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[ClH:31].[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][CH:15]([NH:16][CH2:30][CH2:29][CH2:28][CH:27]([C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:17])=[CH:18][CH:19]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(N)Cc1ccc(OCc2ccccc2)cc1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(Cc1ccc(OCc2ccccc2)cc1)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 60 h

Procedure:
The mixture of 11.1 g of dl-p-benzyloxyamphetamine hydrochloride, 11.2 g of 4,4-di-(4-fluorophenyl)-butyl chloride, 10.34 g of diisopropyl-ethylamine and 50 ml of dimethylformamide is stirred at 100° for 60 hours. It is evaporated, the residue taken up in benzene and the solution washed three times with water. The organic layer is dried, evaporated, the residue taken up in diethyl ether and the solution acidified with hydrogen chloride in isopropanol to afford the dl-1-(p-benzyloxyphenyl)-2-[4,4-di-(4-fluorophenyl)-butylamino]-propane hydrochloride, melting at 130°-133°.
Reaction SMILES: [CH2:1]([N:3]([CH2:43][CH3:44])[C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][C:29]=4[O:30][C:6]=2[CH:5]=1)[N:26]=[C:25]([CH:31]=CC1C=CC(N(C)C)=CC=1)[CH:24]=[C:23]5[CH3:42])[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:12](=[O:19])[O:11]3)[CH3:2].[N+:45]([C:48]1[CH:55]=[CH:54][C:51]([CH:52]=O)=[CH:50][CH:49]=1)([O-:47])=[O:46].C(OC(=O)C)(=O)C.N>O>[CH2:43]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]2[C:10]3([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][C:29]=4[O:30][C:6]=2[CH:5]=1)[N:26]=[C:25]([CH:31]=[CH:52][C:51]1[CH:54]=[CH:55][C:48]([N+:45]([O-:47])=[O:46])=[CH:49][CH:50]=1)[CH:24]=[C:23]5[CH3:42])[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:12](=[O:19])[O:11]3)[CH3:44]
Reactant: CCN(CC)c1ccc2c(c1)Oc1cc3nc(C=Cc4ccc(N(C)C)cc4)cc(C)c3cc1C21OC(=O)c2ccccc21
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: N
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc2c(c1)Oc1cc3nc(C=Cc4ccc([N+](=O)[O-])cc4)cc(C)c3cc1C21OC(=O)c2ccccc21
Temperature: 160 °C
Yield: 51.4 %

Procedure:
2.3 grams (0.005 moles) of 9-(diethylamino)-2-(4-dimethylaminostyryl)-4-methylspiro [6H-[1] benzopyrano [3,2-g] quinoline-6,1'(3'H)-isobenzofuran]-3'-one, 0.6 grams (0.005 moles) of p-nitrobenzaldehyde and 0.5 grams (0.005 moles) of acetic anhydride were mixed in a flask fitted with a reflux condensor, then heated in an oil bath at 160° C. for 4 hours. The bath was cooled and 50 ml of water was added. The mixture was then made alkaline with ammonia, extracted with 100 ml of toluene, dried over sodium sulfate, treated with activated charcoal (DARCO) and filtered. The volume of the solution was reduced to 25 ml by evaporation of the toluene. Ligroine was added to precipitate the product. The yellow-orange solids were filtered off and dried to yield 1.5 grams of product. The reaction sequence was as follows: ##STR15##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:5](Cl)=[O:6].O[NH:17][C:18](=[NH:38])[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][N:23]=[C:24]2[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:17]=[C:18]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[N:38]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Reactant: O=C(Cl)c1ccc(OCC2CC2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC5CC5)c(Cl)c4)n3)cccc12
Reaction time: 1.5 h
Yield: 16.1 %

Procedure:
A solution of 3-chloro-4-[(cyclopropylmethyl)oxy]benzoyl chloride (D16; 73.5 mg, 0.3 mmol) in dry DMF (1.5 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 85 mg, 0.270 mmol) and triethylamine (0.063 ml, 0.450 mmol) in dry DMF (1.5 ml) at 0° and the mixture was stirred at 0° for 1.5 h. The mixture was then heated at 100° with stirring under nitrogen for 16 h. The cooled mixture was partitioned between saturated aqueous sodium bicarbonate (30 ml) and ethyl acetate (3×20 ml), and the organic layer was washed with 50:50 brine:water and brine, dried (MgSO4) and evaporated in vacuo to give a brown oil. The crude product was purified by flash chromatography on silica gel, eluting with 0-30% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (22 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([CH3:13])[C:8]=1[OH:12])[O:5][C:4](=[O:14])[CH:3]=[C:2]2[CH3:1])([O-:17])=[O:16]
Reactant: Cc1cc(=O)oc2c(C)c(O)ccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)oc2c(C)c(O)c([N+](=O)[O-])cc12
Reaction time: 3 h
Yield: 81 %

Procedure:
4,8-Dimethyl-7-hydroxycoumarin (7.50 g, 39.4 mmoles) was dissolved in 75 ml concentrated sulfuric acid at room temperature and chilled to −20° C. before the addition of chilled nitrating mixture (3 ml concentrated nitric acid added to 9 ml concentrated sulfuric acid). Stirring was continued for three hours at −20° C. with the mixture allowed to warm before pouring into ice. Bright yellow crystals were filtered, washed with water and dried to recover 7.50 g (81% yield). The product was recrystallized from ethanol to give yellow green crystals: mp 229.5-231.5° C.; 1H-nmr (dimethyl sulfoxide-d6):δ 2.29 (s, 3H), 2.41 (s, 3H), 6.37 (s, 1H), 8.19 (s, 1H), 11.30 (s, 1H); 13C-nmr (dimethyl sulfoxide-d6):δ 8.8, 18.0, 112.4, 112.9, 115.1, 119.9, 132.8, 152.9, 154.2, 155.1, 159.0; ms: (EI) m/z (relative intensity) 236 (M+, 23), 235 (M+, base) 207 (84), 77 (30).
Reaction SMILES: CC(C)=O.[C:5]([OH:9])(=[O:8])[CH2:6][OH:7].[C:10](Cl)(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[C:10]([O:7][CH2:6][C:5]([OH:9])=[O:8])(=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C(O)CO
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCCCCCCC(=O)OCC(=O)O
Reaction time: 1 h
Yield: 66.7 %

Procedure:
15.8 gm (0.20 mole) pyridine and 50 ml. acetone were combined in a 250 ml. round bottomed-three necked flask equipped with magnetic stir bar and two addition funnels, and cooled in an ice water bath with stirring. One addition funnel was charged with 15.5 gm (0.20 mole) glycolic acid dissolved in approximately 75 ml. acetone. The other addition funnel was charged with 32.5 gm (0.20 mole) octanoyl chloride. The contents of each addition funnel were added simultaneously to the cooled, stirred pyridine solution so that the complete addition of each component was continuous over one hour. The resultant slurry (a precipitation of pyridine hydrochloride was noted) was stirred an additional 45 minutes at ice bath temperature, and then at room temperature for another 30 minutes. Solvent was then removed by rotary evaporation at reduced pressure and 45C. The residual oil was dissolved in 200 ml dichloromethane and this was extracted with 3×150 ml. of 4% aqueous HCl. The dichloromethane layer was dried over sodium sulfate, decanted and the solvent removed by rotary evaporation. Drying on high vacuum for 4 hours left OOAA and 8.0% octanoic acid by weight, giving a crude yield for OOAA of 84%(mole). Recrystallization from 200 ml. hexane gave 27 g of a white crystalline product melting at 50 to 52° C., which was determined to be 99% wt. OOAA, giving a 67% (mole) yield of pure octanoxyloxyacetic acid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([S:11](Cl)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[C:16]1([O:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:5]1([S:11]([C:19]2[CH:20]=[CH:21][C:16]([O:22][CH3:23])=[CH:17][CH:18]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(S(=O)(=O)c2ccccc2)cc1
Yield: 101 %

Procedure:
To a solution of 16 g of AlCl3 dissolved in 21.6 g of anisol was added dropwise 17.6 g of benzenesulfonyl chloride. The reaction mixture was heated to reflux for 8 hours and poured into 1N HCl solution containing ice. The resultant solution was extracted with ethyl acetate (100 ml×3), washed with 100 ml of saturated NaHCO3 aqueous solution, dried over Na2SO4 and concentrated to obtain residue, which was recrystallized from hexane-ethyl acetate to obtain 25 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:14][C:15]2[CH:20]=[C:19]([CH3:21])[C:18](Br)=[C:17]([CH3:23])[CH:16]=2)[CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[F-].[K+].[CH:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([CH3:29])[CH3:28]>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:14][C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([C:33]3[CH:34]=[CH:35][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=3)=[C:17]([CH3:23])[CH:16]=2)[CH:11]([CH3:13])[CH3:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(Oc2cc(C)c(Br)c(C)c2)C(C)C)cc1
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: [F-]
Agent: [K+]
Product: COC(=O)c1ccc(C(Oc2cc(C)c(-c3ccc(C(C)C)cc3)c(C)c2)C(C)C)cc1
Yield: 92.5 %

Procedure:
Isomer 1 of 4-[1-(4-bromo-3,5-dimethyl-phenoxy)-2-methyl-propyl]-benzoic acid methyl ester (500 mg, 1.28 mmol), potassium fluoride (223 mg, 3.84 mmol), 4-isopropylphenyl boronic acid (419 mg, 2.56 mmol) and tetrakis-(triphenylphosphine)palladium (148 mg, 0.128 mmol) are placed in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give the titled compound (510 mg).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:12]([Cl:20])=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[N-:22]=[N+:23]=[N-:24].[Na+].O>CS(C)=O>[N:22]([CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:12]([Cl:20])=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN=[N+]=[N-])c2F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
3-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.65 g, 1.587 mmol) and sodium azide (0.114 g, 1.746 mmol) were combined in DMSO (7 mL) and stirred overnight at 25° C. Water was added to the reaction mixture to give a white precipitate. The reaction mixture was stirred for 15 min at room temperature, filtered, washed with water, and air dried to give 3-{[3-(azidomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.565 g, 1.521 mmol, 96% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (d, J=2.20 Hz, 1H), 7.50-7.63 (m, 2H), 7.31 (d, J=1.74 Hz, 1H), 4.61 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH2:15]>CCOCC>[CH3:14][NH:15][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CN
Solvent: CCOCC
Product: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
To a suspension of 4-nitrobenzenesulfonyl chloride (5 g, 22.56 mmol) in ether (250 ml), methylamine (5 ml, 40% aq. solution, 56.4 mmol) was added, and the mixture was stirred at room temperature. After 16 hr, the reaction mixture was concentrated to remove the solvent and the residue was resuspended in methylene chloride. After washing with 2N HCl and brine, the organic fractions were dried (MgSO4), filtered and concentrated to give N-methyl-4-nitrobenzenesulfonamide (4.8 g, 98%): mp (DSC) 109° C. Anal Calc'd. for C7H8N2O4S: C, 38.89; H, 3.73; N, 12.96. Found: C, 38.83; H, 3.72; N, 12.96.