Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[S:15][CH:14]=[CH:13][C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[C:16](Cl)(=[O:18])[CH3:17].O>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[S:15][CH:14]=[CH:13][C:8]=2[N:9]=[C:10]([NH:12][C:16](=[O:18])[CH3:17])[N:11]=1
Reactant: Nc1nc(-c2ccco2)c2sccc2n1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(-c2ccco2)c2sccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
An ice-cold solution of 4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (130 mg, 0.6 mmol) in pyridine (1 mL) was treated with acetyl chloride (47 μL, 0.66 mmol), stirred at room temperature for 16 h, poured into water, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo and purified by chromatography (SiO2:EtOAc:Heptane, 1:1) to give the title compound (125 mg, 80%) as a cream solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([N:41]1[CH2:45][CH2:44][CH:43](O)[CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[Br:47][C:48]1[CH:53]=[CH:52][N:51]=[C:50]([OH:54])[CH:49]=1>C1COCC1.O>[Br:47][C:48]1[CH:53]=[CH:52][N:51]([CH:43]2[CH2:44][CH2:45][N:41]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:42]2)[C:50](=[O:54])[CH:49]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1cc(Br)ccn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(Br)cc2=O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 109.9 %

Procedure:
To an ice cold solution of triphenylphosphine (0.17 g, 0.63 mmol) in THF (10.0 mL) was added DIAD (0.12 mL, 0.63 mmol) and the resulting solution was stirred at the same temperature for 15 min. after which a yellow precipitate was formed. 1-Boc-3-hydroxypyrrolidine (0.10 g, 0.53 mmol) was then added to the reaction mixture and allowed to stir for 20 min followed by addition of 4-bromo-2-hydroxypyridine (0.093 g, 0.53 mmol). The resulting reaction mixture was stirred for 16 h at room temperature. After completion of reaction (TLC monitoring), the reaction mixture was diluted with water and extracted with EtOAc (3×50 ml). The combined organics was dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel (100-200 M, 0.5% MeOH-DCM) to obtain the desired product (0.20 g, quantitative yield). MS: 343.10 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>C1COCC1>[C:19]([O:18][C:16]([N:10]1[CH2:15][CH2:14][N:13]([C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=2)[CH2:12][CH2:11]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 145 °C
Yield: 69.5 %

Procedure:
To a solution of 4,6-dichloro-2-methylpyrimidine (300 mg, 1.84 mmol) in THF (4 mL) were added tert-butyl piperazine-1-carboxylate (376 mg, 2.02 mmol) and DIPEA (0.48 mL, 2.76 mmol), and the reaction was heated at 145° C. under microwave irradiation for 30 minutes. The resulting mixture was concentrated in vacuo and the residue was partitioned between DCM (50 mL) and water (50 mL). The organic fraction was washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound (400 mg, 70%) as an off-white solid. LCMS (ES+) 313.0 (M+H)+, RT 3.63 minutes (Method 1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[Si:5](Cl)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: OCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.2 %

Procedure:
To a solution of 2-bromoethanol (5.0 g, 40.3 mmol) in DCM (20 mL) was added tert-butyldimethylsilyl chloride (9.1 g, 60.5 mmol) followed by the additions of triethylamine (8.14 g, 80.6 mmol) and 4-dimethylaminopyridine (49.2 mg, 0.4 mmol). The mixture was stirred at room temperature for 15 h and concentrated in vacuo. The residue was partitioned between 1N HCl and ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford yellow oil, which was purified by column chromatography eluting with PE:EA (50:1) to afford 123a as colorless oil (6.0 g, 62.4%). LCMS: (M+H)+ 241.
Reaction SMILES: [NH:1]([C:8]([NH:10][C:11]1[CH:31]=[CH:30][C:14]([CH2:15][C@H:16]2[CH2:20][O:19]C(C)(C)[N:17]2C(OC(C)(C)C)=O)=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:32]>CO.C(OCC)(=O)C>[ClH:32].[NH2:17][C@H:16]([CH2:20][OH:19])[CH2:15][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(NC(=O)Nc3ccccc3)cc2)COC1(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: N[C@H](CO)Cc1ccc(NC(=O)Nc2ccccc2)cc1
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (S)-4-[4-[(anilinocarbonyl)amino]benzyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.48 g) in methanol (20 ml) was added 4N hydrogen chloride in ethyl acetate (5 ml) at room temperature, and the solution was stirred at the same temperature for 4 hours. The mixture was evaporated in vacuo, and the residue was triturated with diisopropyl ether to give (S)-N-[4-(2-amino-3-hydroxypropyl)phenyl]-N′-phenylurea hydrochloride (660 mg) as a colorless solide.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][C:13]3[CH:14]=[C:15]([C:19]4([C:25]#[N:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:3]=1.CCO.O.[NH2:31][NH2:32]>>[NH:31]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][C:13]3[CH:14]=[C:15]([C:19]4([C:25]#[N:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:3]=1)[NH2:32]
Reactant: N#CC1(c2cccc(Sc3ccc4nc(Cl)ccc4c3)c2)CCOCC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#CC1(c2cccc(Sc3ccc4nc(NN)ccc4c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5h (4.4 g, 11.6 mmol) was suspended in hydrazine hydrate (11 mL) and EtOH (45 mL) and heated to 80° C. overnight. The reaction was cooled to room temperature and concentrated, and then diluted with EtOAc and water. The aqueous layer was extracted with EtOAc twice, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in CH2Cl2 (15 mL) and heated to dissolve as much of the material as possible. Hexanes (45 mL) was added slowly, and the mixture was stirred for 30 minutes. The precipitate was filtered, rinsed with hexanes, and dried to give the desired product, 5i.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:12]O)[C:8]2=[O:11])=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=[O:21])=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]#[N:12])=[C:9]([CH:10]=1)[C:8]([OH:11])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1C(=NO)Cc2ccc(Br)cc21
Product: N#CCc1ccc(Br)cc1C(=O)O

Procedure:
Similar procedure as described in example 9B was used, starting from 6-Bromo-indan-1,2-dione 2-oxime and p-Toluenesulfonyl chloride to give 5-Bromo-2-cyanomethyl-benzoic acid. LC-MS: m/e: 238 (M−1).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][N:3]=1.C1COCC1>CO.[Pt]>[NH2:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: O=[N+]([O-])c1ccnc(Br)c1O
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccnc(Br)c1O

Procedure:
A solution of 5.3 g (22.7 mmol) 2-bromo-4-nitro-pyridin-3-ol in 100 ml MeOH:THF=1:2 is hydrogenated in the presence of 0.5 g Pt/C (5%, Engelhard 4709). The reaction mixture is filtered (2 glass fiber filters used) and the filtrate is concentrated in vacuo to afford the crude title compound as a brown solid.
Reaction SMILES: [CH3:1][SiH:2]([CH:6]([CH3:8])[CH3:7])[CH:3]([CH3:5])[CH3:4].[Br:9]Br.Br>>[CH3:1][Si:2]([CH:6]([CH3:8])[CH3:7])([CH:3]([CH3:5])[CH3:4])[Br:9]
Reactant: CC(C)[SiH](C)C(C)C
Reactant: BrBr
Agent: Br
Product: CC(C)[Si](C)(Br)C(C)C
Reaction time: 1 h

Procedure:
20.8 g (0.16 mol) of the methyldiisopropylsilane prepared under Example 2, above, was placed in a 50 mL three-neck flask equipped with a reflux condenser, thermometer, and addition funnel. 25 g bromine (0.16 mol) was cautiously dripped in while cooling with ice and stirring with a magnetic stirring bar. A strong exothermic reaction developed, and hydrogen bromide was evolved. After addition of the entire quantity of bromine, the reaction was allowed to stand for 1 hour at room temperature and was then distilled in vacuo. 26.3 g (0.13 mol) of the target methyldiisopropylbromosilane (bp=92 degrees Centigrade/50 mmHg) was obtained.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:26]2[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([O:36]C(C)(C)C)=[O:35])=[CH:28][CH:27]=2)=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:18][CH3:19])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:26]2[CH:27]=[CH:28][C:29](/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35])=[CH:30][CH:31]=2)=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:18][CH3:19])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC/C(=C(\c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccc(OC(=O)c2ccccc2)cc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OC(=O)c2ccccc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Compound 19 was dissolved in CH2Cl2 (10 mL) and cooled to 0° C. in an ice bath. TFA (5 mL, 65 mmol) was and the mixture stirred in an ice bath for 2 h. The reaction was concentrated at RT and dried under high vacuum to provide the title compound, 18, as a white solid (53 mg, 74%). 1HNMR (400 MHz, DMSO-d6): δ 0.86 (t, 3H), 2.40 (q, 2H), 6.51 (d, J=16 Hz, 1H), 6.90 (d, J=8 Hz, 2H), 6.96 (d, J=8 Hz, 2H), 7.14-7.18 (m, 3H), 7.16-7.20 (m, 4H), 7.54 (d, J=8 Hz, 2H), 7.56 (d, J=16 Hz, 1H), 7.66-7.71 (m, 3H), 8.03 (d, J=8 Hz, 2H), 12.2 (br s, 1H); MS, m/z, 473 (M−H)−.
Reaction SMILES: [NH2:1][C:2](=[O:34])[C:3]([C:5]1[C:9]2[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[N:11][CH:12]=[CH:13][C:8]=2[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2C2C=CC=CC=2)[C:6]=1[CH2:32][CH3:33])=[O:4].[OH-].[K+].O.[OH-].[Li+]>CO.O>[NH2:1][C:2](=[O:34])[C:3]([C:5]1[C:9]2[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[N:11][CH:12]=[CH:13][C:8]=2[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:6]=1[CH2:32][CH3:33])=[O:4]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)nccc2n1Cc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)nccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(3-(2-amino-2-oxoacetyl)-1-(biphenyl-2-ylmethyl)-2-ethyl-1H-pyrrolo[3,2-c]pyridin-4-yloxy)acetic acid, Ily-II-10: Compound 21 (0.227 mmol) is dissolved in methanol (20 mL). To the mixture the solution of KOH (1M, 0.25 mL) is added at room temperature. After addition the mixture was stirred at room temperature for 18 h. Then solution of lithium hydroxide monohydrate (90 mg) in H2O (5 mL) is added. After another hour stirring the mixture was concentrated and the residue is redissolved in methanol (10 mL) and ethanol (10 mL). The mixture is filtered and the filtrate was acidified by hydrogen chloride in ether (1.0 M) to pH=3-4. Solvent is evaporated and the residue is washed with a mixture of dichloromethane: ether (1:1), then water (5 mL) and ether to afford 2-(3-(2-amino-2-oxoacetyl)-1-benzyl-2-ethyl-1H-pyrrolo[3,2-c]pyridin-4-yloxy)acetic acid, Ily-II-10.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:18])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[NH:10][C:9](=[O:15])[C:8]([CH3:16])=[C:7]2[CH3:17])[CH:2]=[CH2:3].[Br:19]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:19][CH2:3][CH:2]1[O:18][C:5]2=[C:6]3[C:11](=[C:12]([CH3:14])[CH:13]=[C:4]2[CH2:1]1)[NH:10][C:9](=[O:15])[C:8]([CH3:16])=[C:7]3[CH3:17]
Reactant: C=CCc1cc(C)c2[nH]c(=O)c(C)c(C)c2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1c(C)c2c3c(cc(C)c2[nH]c1=O)CC(CBr)O3
Temperature: 100 °C
Yield: 79.1 %

Procedure:
6-Allyl-5-hydroxy-3,4,8-trimethylcarbostyril (1.01 g, 4.16 mmol) was dissolved in chloroform (50 ml). To the obtained solution, N-bromosuccinimide (888 mg, 4.99 mmol) was added. The mixture was refluxed with in a bath of 100° C. for 1.5 hours. The reaction mixture was cooled, washed with saturated aqueous NaCl solution and dried. The solvent was distilled off under reduced pressure. The residue was recrystallized from chloroform--ether to obtain 1.06 g of the title compound as yellow needles (79.8%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]([CH2:10][CH2:11][OH:12])[CH3:9]>[Pd].C(O)C.CO.N>[CH3:9][N:8]([CH2:10][CH2:11][OH:12])[C:7]1[CH:6]=[CH:5][N:4]=[N:3][CH:2]=1
Reactant: CN(CCO)c1cc(Cl)nnc1Cl
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: CCO
Product: CN(CCO)c1ccnnc1
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A mixture of 2-(N-(3,6-dichloropyridazin-4-yl)-N-methylamino)ethanol (444 mg, 2 mmol) and 10% palladium-on-charcoal catalyst (150 mg) in ethanol (15 ml), methanol (5 ml) and aqueous ammonia (15 ml) was stirred under hydrogen at 3 atmospheres pressure for 4 hours. The catalyst was removed by filtration and the solvent removed from the filtrate by evaporation. The residue was dissolved in methylene chloride, the insoluble material was removed by filtration and the solvent was removed from the filtrate by evaporation. The residue was purified by column chromatography on neutral aluminum oxide eluting with methylene chloride/methanol (95/5 followed by 90/10). The purified product was triturated with petroleum ether, the solid product was collected by filtration and dried under vacuum to give 2-(N-methyl-N-(pyridazin-4-yl)amino)ethanol (275 mg, 91%).
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])=[O:4].[C:18]([NH:35][C@H:36](C(O)=O)C)([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH:24]1[C:23]2[CH:22]([CH2:21][O:20][C:18]([NH:35][CH2:36][CH2:2][C:3]([O:5][C:6]3[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=3[F:15])=[O:4])=[O:19])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCNC(=O)OCC1c2ccccc2-c2ccccc21)Oc1c(F)c(F)cc(F)c1F
Reaction time: 1 h

Procedure:
2,3,5,6-Tetrafluorophenyl trifluoroacetate (1.7 g, 6.5 mmol) was added dropwise to a solution of FMOC-alanine (2.0 g, 6.4 mmol) and triethylamine (1.0 ml, 7 mmol) in 20 ml of anhydrous CH2Cl2. After 1 hr., CH2Cl2 was removed by evaporation at reduced pressure using rotary evaporator, redissolved in 30 ml ethylacetate/hexane (1:1). Flash chromatography (4×20 cm, hexane/ethyl acetate, 3:1) afforded rude 4 as a white solid. It was recrystallized from hexane/ethyl acetate to give 4 as a white crystalline solid (2.3 g, 78%): 1H NMR (CDCl3, 200 MHz, ppm) 7.73 (d, 2H, J=7.1 Hz, aromatic protons), 7.75 (d, 2H, J=7.7 Hz, aromatic protons), 7.24-7.42 (m, 411, aromatic protons), 7.01 (m, 1H, C6F4H), 5.21 (br s, 1H, —CONH—), 4.38 (d, 2H, J=7.1 Hz, —CH2OCO—), 4.20 (m, 1H, benzyl proton), 3.58 (m, −2H, NCH 2), 2.93 (t, 2H, J=5.4 Hz, —CH2CO—). Anal. Calcd. for C24H17NO4F4: C, 62.75; H, 3.73; N, 3.05. Found: C, 62.52; H, 3.59; N, 3.01.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH3:14])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[CH3:17])[C:6]2=O.C([SnH](CCCC)CCCC)CCC.[F-].[K+]>C1C=CC=CC=1>[CH3:12][O:11][C:10]1[CH:2]=[C:3]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=1)[CH2:6][N:5]([CH:16]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[CH3:17])[CH2:4]2
Reactant: COc1cc(OC)c2c(c1Br)CN(C(C)c1ccc(Cl)cc1)C2=O
Agent: CCCC[SnH](CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc2c(c(OC)c1)CN(C(C)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Yield: 65.3 %

Procedure:
To a solution of 4-bromo-5,7-Dimethoxy-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1 one (0.112 g, 0.27 mmol) in benzene under N2 atmosphere was added 2,2′-azobis(2-methyl propionitrile) AIBN (5.0 mg), followed by tributyl tin hydride (0.145 mL, 0.55 mmol). The resulting mixture was refluxed in an oil bath for 2 h. The reaction was monitored by GC-MS for the disappearance of starting material. The reaction mixture was cooled to room temperature and stirred with potassium fluoride (200 mg) for 45 min. The solids were filtered and the filtrate was concentrated. The resulting material was purified using column chromatography (typically 40% ethyl acetate in hexanes) to give 5,7-Dimethoxy-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-lone (0.056 g, 63%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.43 (d, 3H), 3.63 (s, 3H), 3.68 (d, 1H), 3.74 (s, 3H), 3.99 (d, 1H), 5.53 (q, 1H), 6.23 (dd, 2H), 7.15 (m, 4H). GC-MS: m/z 331 (M)+, 316 (M−15)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:38][CH3:39])([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:25]([CH3:37])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:40])[CH:10]=[C:11]([OH:13])[CH:12]=1.Cl>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:9]2[CH:10]=[C:11]([OH:13])[CH:12]=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=2)=[C:15]([CH3:40])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH:31]([OH:36])[C:32]([CH3:34])([CH3:35])[CH3:33])=[C:25]([CH3:37])[CH:24]=1)[CH2:38][CH3:39])[CH3:22]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cc(O)cc(CC(=O)OC)c2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cc(O)cc(CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.7 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.10 mL) was added to a solution of (4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-5-hydroxy-2′-methyl-biphenyl-3-yl)acetic acid methyl ester (Example 164-(4); 17.5 mg, 0.0330 mmol) in methanol (0.40 mL) at room temperature, and the mixture was stirred at room temperature for seven hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (17 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][O:19][CH3:20].[N+:21]([O-])([OH:23])=[O:22]>CC(O)=O>[CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:5][C:6]([C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8])=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=1
Reactant: COCCOC(=O)c1ccc(OC)c(OCCOC)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COCCOC(=O)c1cc(OCCOC)c(OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-methoxyethyl 4-methoxy-3-(2-methoxyethoxyl)benzoate (15.05 g, 52.9 mmol) in AcOH (54 mL) under an atmosphere of N2 was added conc. HNO3 (13.5 mL) in one portion. The reaction was stirred at RT for 72 h. The mixture was poured into ice-water (ca. 800 mL) and extracted with EtOAc (2×400 mL). The combined organics were washed with water (2×200 mL) and brine (1×200 mL), dried (Na2SO4) and conc. in vacuo. The residue was azeotroped with heptane (2×300 mL) to remove residual AcOH giving 2-methoxyethyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate as a dark colored oil. (15.5 g, 47.1 mmol, 89%). HPLC retention time 6.24 mins.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:10][CH2:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH2:23][Br:24])=[O:20]>ClCCl>[Br:24][CH2:23][CH2:22][O:21][C:19]([N:10]1[CH2:9][CH2:8][CH2:7][S:6][C:5]1=[CH:4][N+:1]([O-:3])=[O:2])=[O:20]
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: O=C(Cl)OCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCBr)N1CCCSC1=C[N+](=O)[O-]
Temperature: 0 °C
Yield: 79.2 %

Procedure:
To a mixture of 12.8 g 2-nitromethylene-tetrahydro-2H-1,3-thiazine, 21 ml triethylamine and 120 ml dichloro methane was added dropwise over 75 minutes, at -30° C. under nitrogen, a solution of 18 g 2-bromoethyl chloroformate in 100 ml dichloro methane. The reaction mixture was allowed to warm to 0° C., over 30 minutes, with stirring, and then washed with 2% hydrochloric acid. The organic phase was separated off and dried (MgSO4), and the solvent was evaporated off. The solid material (27.2 g) was purified on a silica gel column using a 199:1 mixture (vol/vol) of dichloro methane and methanol, to yield 19.7 g of crystals, having a melting point of 79°-81° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15]>O1CCCC1>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][C:14](=[O:15])[C:13]([F:20])([F:19])[F:12])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CCOC(=O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(NC(=O)C(F)(F)F)cc(OC)c1
Yield: 97.4 %

Procedure:
To 3,5-dimethoxyaniline (20 g, 131 mmol) dissolved in anhydrous tetrahydrofuran (90 mL) was added 4-(dimethylamin) pyridine (1.6 g, 13.1 mmol) and ethyl trifluoroacetate (47 mL, 392 mmol). After refluxing 48 hours, the cooled reaction mixture was concentrated and partitioned between ethyl acetate (300 mL) and 2N hydrochloric acid (100 mL). The ethyl acetate layer is washed with water (100 mL), dried using anhydrous sodium sulfate, and concentrated to yield N-(3,5-dimethoxyphenyl)-2,2,2-trifluoroacetamide (31.8 g, 98%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13]>CC(C)=O>[CH2:12]([NH:14][C:15]([NH:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[S:16])[CH3:13]
Reactant: NC1CCCc2ccccc21
Reactant: CCN=C=S
Solvent: CC(C)=O
Product: CCNC(=S)NC1CCCc2ccccc21
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a stirred solution of 8.84 grams (0.060 mole) of 1,2,3,4-tetrahydro-1-naphthylamine in 100 ml of acetone, under a blanket of nitrogen, is added a solution of 6.27 grams (0.072 mole) of ethyl isothiocyanate in 50 ml of acetone. The reaction mixture is stirred overnight, and the solvent then evaporated at reduced pressure. Toluene is added to the residue, and the mixture is then evaporated at reduced pressure. The residue is crystallized from nitromethane to give 7.08 grams of the product, melting point 120°C. to 122°C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:22])=[C:4]([CH2:11][CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:10])=[C:6]([NH2:9])[C:7]=1[I:8].[C:23]([O:26][CH2:27][C:28](Cl)=[O:29])(=[O:25])[CH3:24]>C(Cl)Cl.C(#N)C>[C:23]([O:26][CH2:27][C:28]([NH:9][C:6]1[C:5]([I:10])=[C:4]([CH2:11][CH:12]([O:18][C:19](=[O:21])[CH3:20])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:3]([I:22])=[C:2]([NH:1][C:12](=[O:18])[CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:7]=1[I:8])=[O:29])(=[O:25])[CH3:24]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(=O)OCC(Cc1c(I)c(N)c(I)c(N)c1I)OC(C)=O
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)OCC(=O)Nc1c(I)c(CC(COC(C)=O)OC(C)=O)c(I)c(NC(=O)COC(C)=O)c1I
Yield: 64 %

Procedure:
The product in Example 64e, 3,5-diamino-2,4,6-triiodo-(2,3-diacetoxypropyl)benzene was acylated using acetoxyacetyl chloride according to the general procedure in Example 24i. After chromatography on silica gel using methylene chloride/acetonitrile (3/1) as the eluent the product was isolated in 64% yield.