Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)=[O:7].[H-].[Na+].[CH2:32](Cl)[C:33]#[CH:34]>CN(C=O)C>[CH2:34]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH2:13][CH2:12]3)=[CH:23][CH:22]=2)[CH2:17][CH2:18][C:19]1=[O:24])[C:33]#[CH:32]
Reactant: C#CCCl
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)CCc2cc(N3CCN(C(=O)c4ccc(OC)c(OC)c4)CC3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.8 %

Procedure:
6-[4-(3,4-Dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (1.96 g) and 0.25 g of 50% oily sodium hydride were mixed with 60 ml of DMF and stirred at room temperature for 2 hours. Then, to the mixture was added 0.66 g of propargyl chloride and the mixture was stirred at room temperature for 7 hours. The reaction mixture was poured into a 150 ml of saturated saline solution and organic substances were extracted with chloroform. The chloroform layer was washed with water and dehydrated. Chloroform was distilled off and the residue was purified through silica gel column chromatography followed by recrystallization from ethanol to give 0.34 g of 1-(2-propynyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 152°-154° C., pale yellow needles.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][O:12][CH2:11]2)=[C:6]([O:16][CH3:17])[C:5]([O:18][CH:19]([F:21])[F:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[C:41](=[O:45])[NH:40][CH2:39]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][CH:19]([F:21])[O:18][C:5]1[CH:4]=[CH:3][C:2]([C:36]2[CH:37]=[C:38]3[C:42](=[CH:43][CH:44]=2)[C:41](=[O:45])[NH:40][CH2:39]3)=[C:7]([O:8][CH2:9][C:10]2([CH2:14][OH:15])[CH2:13][O:12][CH2:11]2)[C:6]=1[O:16][CH3:17]
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: COc1c(OC(F)F)ccc(Br)c1OCC1(CO)COC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)CNC3=O)c1OCC1(CO)COC1
Temperature: 85 °C
Yield: 21.9 %

Procedure:
To a stirring solution of (3-((6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)oxetan-3-yl)methanol (200 mg, 0.541 mmol) in dimethylformamide (10 mL) was purged with argon for 1 h. To this cesium carbonate (527 mg, 1.623 mmol), tetrakis(triphenylphosphine) palladium(0) (31 mg, 0.027 mmol) and 5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (168 mg, 0.650 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (50 mg, 21%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2.[OH:25]O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]2)=[O:25]
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCCSc3ccccn3)ccc2N1
Product: O=C1CCc2cc(OCCCCCS(=O)c3ccccn3)ccc2N1

Procedure:
Prepared analagous to Example 2 from 6-[5-(2-pyridyl-mercapto)-pentoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[O:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.O.NN.[CH3:27]O>[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:27]=1
Reactant: COc1ccc([N+](=O)[O-])cc1OCc1cccc2ccccc12
Reactant: CO
Agent: [Ni]
Agent: NN
Solvent: O
Product: COc1ccc(N)cc1OCCc1ccc2ccccc2c1

Procedure:
4-Methoxy-3-(2-naphthylethoxy)phenylamine was prepared using the same experimental conditions described in Scheme XII. From 1-methoxy-2-(naphthylmethoxy)-4-nitrobenzene (3.8 g, 12.3 mmol), hydrazine hydrate (3.1 g, 61.4 mmol) and a catalytic amount of Raney nickel in 100 mL of methanol refluxed for 0.5 h., was obtained 3.5 g of product in (100%) yield as a brown oil that crystallized on standing. MS (EI) m/z 279 (M+).
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:26]Cl)[CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1>CS(C)=O>[F:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:1]#[N:2])[CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(CCl)cc43)CC2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 0 °C
Yield: 98.2 %

Procedure:
Dimethyl sulfoxide (500 ml) and sodium cyanide (9.8 g) were added to 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (about 70 g) and the resultant mixture was stirred at 50° C. for 2 hr. Next, ice water (500 ml) was added to the reaction solution followed by vigorously stirring. The resulting crystals were collected by filtration, washed with water and air-dried at 80° C. to give the title compound (67 g) as a pale yellow powder (yield: 93%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:3]=1.[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH2:25])=[CH:22][CH:21]=1.[OH-].[Na+]>ClCCl>[Cl:8][C:6]1[N:7]=[C:2]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[CH2:25])=[CH:22][CH:21]=2)[N:3]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=1
Reactant: C=Cc1ccc(O)cc1
Reactant: Cc1cc(C)c(Oc2nc(Cl)nc(Cl)n2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=Cc1ccc(Oc2nc(Cl)nc(Oc3c(C)cc(C)cc3C)n2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 25.57 g (0.09 moles) 2,4-dichloro-6-(2,4,6-trimethylphenoxy)-1,3,5-triazine in 300 ml of dichloromethane was treated with 11.8 g (0.098 moles) p-hydroxystyrene (prepared by hydrolysis of p-acetoxystyrene) dissolved in about 40 ml dichloromethane. The mixture was cooled in an ice-water bath and 36.8 g of 10% aqueous sodium hydroxide solution was added with stirring over about 5 minutes. Stirring was continued for 30 minutes after which time the ice-water bath was removed and stirring was continued for about 2 hours. The mixture was treated with brine, the layers were separated, and after standing, the organic layer was washed twice with brine, and once with water, and dried over magnesium sulfate. Filtration and evaporation gave a white solid with proton NMR spectrum consistent with the desired product, 2-chloro-4-(4-ethenylphenoxy)-6-(2,4,6-trimethylphenoxy)-1,3,5-triazine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOCC>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][Br:14]
Reactant: BrCCCCCBr
Reactant: COC(=O)CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)CCc1ccccc1OCCCCCBr
Yield: 586.1 %

Procedure:
A mixture of 3.6 g (20 mmol) of 2-hydroxybenzenepropanoic acid methyl ester, 22 mL (160 mmol) of 1,5-dibromopentane, 8.73 g (63.3 mmol) of anhydrous granular potassium carbonate, and 145 mL of acetonitrile was stirred and refluxed for 24 hr. The resulting slurry was cooled and diluted with 300 mL of ether. The solids were removed by suction filtration and the filter cake was washed well with ether. The filtrate and washes were combined and concentrated in vacuo giving 38.59 g of a brown oil which was chromatographed on 200 g of silica gel, eluting with 49:1 and 19:1 hexane-ether. The fractions containing the desired product were combined and concentrated giving 5.86 g of an oil which was dissolved in 50 mL of methanol containing 0.2 g of p-toluenesulfonic acid monohydrate. The solution was stirred at room temperature for 17 hr and refluxed for 5 hr before being cooled and concentrated in vacuo. The residue was dissolved in ether and the solution was washed with saturated sodium bicarbonate solution and worked-up in the usual manner. The oily residue was chromatographed on 100 g of silica gel. Elution with 19:1 hexane-ether afforded 4.85 g (73.7%) of 2-[5-bromopentyl)oxy]benzenepropanoic acid methyl ester as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([N:24]3[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[N:26]=[N:25]3)[CH:21]=[CH:20][C:19]=2[CH3:32])=[O:17])=[C:12]([CH3:33])[CH:11]=1.BrC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.[Cl:59]C1C=C(N)C=CC=1F>>[Cl:59][C:7]1[CH:2]=[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[N:26]=[N:25]4)[CH:21]=[CH:20][C:19]=3[CH3:32])=[O:17])=[C:12]([CH3:33])[CH:11]=2)[CH:4]=[CH:5][C:6]=1[F:8]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Agent: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1cc(Nc2ccc(F)c(Cl)c2)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 3-chloro-4-fluoro-phenylamine (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 196.4, 152.6 (d), 147.6, 145.8, 142.3, 142.3, 138.6 (d), 135.3 (d), 134.4, 132.2, 126.9, 121.1, 120.7, 120.5, 120.0 (d), 119.9 (d), 118.4, 117.7, 117.5 (d), 111.3, 60.2, 29.2, 22.0, 18.9
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([CH2:44][N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]2)=[CH:14][N:13]=1.[NH2:55][C:56]1[CH:57]=[CH:58][C:59]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[N:60][CH:61]=1>C1COCC1>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:20]2[N:21]=[C:22]([CH3:24])[N:23]=[C:18]([C:17]3[C:12]([NH:55][C:56]4[CH:57]=[CH:58][C:59]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:67])([CH3:66])[CH3:68])=[N:60][CH:61]=4)=[N:13][CH:14]=[C:15]([CH2:44][N:45]4[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]4)[CH:16]=3)[N:19]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
LiHMDS (Aldrich) (2.44 mL, 2.44 mmol) was added dropwise at 0° C. to a stirred solution of 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.507 g, 0.815 mmol) and tert-butyl 5-aminopyridin-2-ylcarbamate (0.204 g, 0.976 mmol) in THF (2 mL). The dark red mixture was stirred at 0° C. for 2 h. More LiHMDS (1.6 mL, 1.6 mmol) was added dropwise at 0° C. and stirring was continued for another 30 min. The reaction was quenched by adding 0.3 mL of sat'd NH4Cl. The reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (2×30 mL). The combined organic layers were washed with saturated aqueous sodium chloride (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (100 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-10%) to give tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)pyridin-2-ylcarbamate (0.306 g, 46% yield). 1H NMR (400 MHz, CDCl3) δ 11.76 (s, 1H); 8.71 (d, J=2.54 Hz, 1H); 8.42 (d, J=2.35 Hz, 1H); 8.23 (d, J=2.35 Hz, 1H); 7.94 (dd, J=9.00, 2.54 Hz, 1H); 7.83 (d, J=9.00 Hz, 1H); 7.15-7.25 (m, 5H); 6.86 (dd, J=11.15, 8.61 Hz, 4H); 4.83 (d, J=10.17 Hz, 4H); 3.76-3.85 (m, 6H); 3.50 (s, 2H); 3.18 (br. s., 4H); 2.71 (s, 3H); 2.59 (s, 3H); 2.55 (t, J=4.50 Hz, 4H); 1.53 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12](Br)[CH:13]=[CH2:14]>>[CH2:14]([C:7]1([OH:11])[CH2:8][CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6]1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: O=C1CCCC2(C1)OCCO2
Product: C=CCC1(O)CCCC2(C1)OCCO2
Yield: 84 %

Procedure:
The title compound is prepared from 1,4-dioxa-spiro[4.5]decan-7-one and allyl bromide following a procedure analogous to that described in Step 1 of Intermediate 2. Yield: 84% of theory; Mass spectrum (ESI+): m/z=181 [M+H—H2O]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1.[I-:28].[Na+].O>CC(CC)=O>[F:26][C@H:16]1[CH2:15][C@@:13]2([CH3:14])[C@@H:9]([CH2:10][CH2:11][C:12]2=[O:27])[C@H:8]2[C@H:17]1[C:18]1[CH:19]=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[CH2:24][C@H:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:28]
Reactant: [I-]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CCC2=O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCI)[C@H]3[C@@H]1CCC2=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 110.3 %

Procedure:
5.0 g of 7α-(5-chloropentyl)-11β-fluoro-3-hydroxyestra-1,3,5(10)trien-17-one are dissolved in 80 ml of ethyl methyl ketone, treated with 5.7 g of sodium iodide and stirred overnight at a bath temperature of 90° C. For work-up, the reaction mixture is cooled to room temperature, stirred into water, extracted 3 times with ethyl acetate, washed with sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. 6.8 g of 11β-fluoro-3-hydroxy-7α-(5-iodopentyl)-oestra-1,3,5(10)-trien-17-one are obtained as a crude product, which is employed in the next stage without further purification.
Reaction SMILES: C(NS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)C.[CH2:20]([N:23]([CH2:40][CH3:41])[S:24]([C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])(=[O:26])=[O:25])[CH:21]=[CH2:22].[CH2:42]([O:44][P:45]([O-:49])[O:46][CH2:47][CH3:48])[CH3:43]>>[CH2:40]([N:23]([CH2:20][CH2:21][CH2:22][P:45]([O:46][CH2:47][CH3:48])(=[O:49])[O:44][CH2:42][CH3:43])[S:24]([C:27]([F:39])([F:38])[C:28]([F:36])([F:37])[C:29]([F:34])([F:35])[C:30]([F:31])([F:32])[F:33])(=[O:26])=[O:25])[CH3:41]
Reactant: C=CCN(CC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCOP([O-])OCC
Agent: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCOP(=O)(CCCN(CC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC

Procedure:
The procedure of Example 1 was repeated with the exception that N-ethylperfluorobutanesulfonamide was used in place of N-butyltrifluoromethanesulfonamide to make N-allyl-N-ethylperfluorobutanesulfonamide (b.p. 50°-55° C. at 0.12 to 0.10 torr). The latter was reacted with diethylphosphite to produce the desired compound, diethyl 3-(N-ethylperfluorobutanesulfonamido)propanephosphonate (b.p. 148°-152° C. at 0.4-0.5 torr). A solution of the phosphonate prepared in Example 3 (30.0 g, 0.062 mole) and bromotrimethylsilane (20.0 g, 0.130 mole) was stirred under a reflux condenser and calcium chloride drying tube for 24 hours, water (75 ml) was added, and the mixture stirred for 15 minutes. The resulting white precipitate was filtered and washed with water (50 ml) and diethylether (100 ml), then dried in an oven at 100° C. for 24 hours at 10-20 torr, to yield the desired compound, 3-(N-ethylperfluorobutanesulfonamido)propanephosphonic acid (m.p. 138.5°-140° C.).
Reaction SMILES: [I:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.[Br:22]Br.CCOC(C)=O>C(O)(=O)C>[Br:22][C:3]1[C:4]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:13][CH:14]=3)[NH:6][C:5]=2[C:18]([O:20][CH3:21])=[CH:19][C:2]=1[I:1]
Reactant: COc1cc(I)cc2nc(-c3ccc(C(C)C)cc3)[nH]c12
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(I)c(Br)c2nc(-c3ccc(C(C)C)cc3)[nH]c12
Reaction time: 0.75 h
Yield: 52.4 %

Procedure:
To a solution of 200 mg (0.51 mmol) 5-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1H-benzoimidazole in 3 ml glacial acetic acid is slowly added 82 mg (0.51 mmol) bromine. The reaction mixture is stirred for 45 min. 30 ml EtOAc are added and this solution is washed 2n NaOH, water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) and recrystallized from EtOAc/diethyl ether to afford 126 mg of the title compound as off-white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][SH:19])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>C1COCC1>[C:27]([S:19][CH2:18][CH2:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: O=C(CCNC(=O)OCc1ccccc1)NCCS
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SCCNC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To the stirred solution of 3-(benzyloxycarbonylamino)-N-(2-mercaptoethyl)propionamide (2 g) and triethylamine (0.8 g) in anhydrous THF (15 ml), acetyl chloride (0.6 g) is added dropwise under ice-water cooling. After the addition, the mixture is stirred for 30 minutes under ice-water cooling and additional 30 minutes at room temperature. The solution is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in ethyl acetate (30 ml) and the solution is washed with saturated sodium bicarbonate solution, N hydrochloric acid and then saturated sodium chloride solution. The ethyl acetate solution is dried over anhydrous magnesium sulfate and concentrated in vacuo to give 1.6 g (70%) of the titled compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9](I)=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31].C(#N)C>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:11]([C:12]2[NH:13][C:14](=[O:27])[C:15]3[C:16](=[C:18]([CH2:25][CH3:26])[N:19]([CH2:21][CH2:22][O:23][CH3:24])[N:20]=3)[N:17]=2)=[CH:10][C:9]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCOc1ncc(I)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
The title compound from Example 1 (127 mg, 0.25 mmol) was suspended in triethylamine (2 mL) and trimethylsilylacetylene (38 mg, 0.39 mmol) and acetonitrile (2 mL to try and solubilise reactants). Pd(PPh3)2Cl2 (5 mg, 0.006 mmol) and cuprous iodide (1.2 mg, 0.006 mmol) were added and the reaction mixture stirred. After 1 h a further portion of trimethylsilylacetylene (19 mg, 0.19 mmol) was added and stirring continued for 2 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organics were washed with brine, dried (MgSO4) and concentrated to give a brown foam. Purification by flash column chromatography (gradient elution from 100% dichloromethane to 99% dichloromethane/methanol) gave the title compound as a light brown solid (108 mg).
Reaction SMILES: [C:1]([NH:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(SC)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C(S)(C)C.C(=O)([O-])[O-].[K+].[K+].CO.O>O>[C:1]([NH:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CSC(NC(C)=O)(C(=O)O)c1ccccc1
Agent: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)NC(C(=O)O)c1ccccc1
Yield: 90 %

Procedure:
340 Milligrams of N-acetylamino-α-methylthiophenylacetic acid, 240 mg of isopropyl mercaptan, and 351 mg of potassium carbonate were added to 10 ml of a methanol-water mixture (9:1), and refluxed for 3 hours. Following a reduced pressure concentration of the reaction mixture to approximately 1 ml, 20 ml of water was added to the concentrate, which was then extracted with ethyl acetate. The organic phase was dried with Glauber's salt, and concentrated under reduced pressure. The residue was crystallized from an ether-n-hexane system, to provide 247 mg of α-acetylaminophenylacetic acid. The yield was 90%.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:18]([O:20]CC)=[O:19])=[CH:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:18]([OH:20])=[O:19])=[CH:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2ccc(Cc3ccccc3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2ccc(Cc3ccccc3)cc2c1
Yield: 65.8 %

Procedure:
A solution of ethyl 6-benzylquinoline-3-carboxylate (C, 1.85 g) and 1 N sodium hydroxide solution (7 mL) in ethanol (10 mL) was refluxed for 1.5 hr. After the solvents were removed in vacuo, the residue was diluted with water and washed with ethyl ether. The aqueous layer was acidified with 1 N hydrochloric acid, and the precipitate was collected by filtration to afford the title compound (1.10 g) as a pale yellow powder: mp 203-205° C.; 1H NMR (400 MHz, CD3OD) δ 4.22 (s, 2H), 7.10-7.38 (m, 5H), 7.62-7.85 (m, 2H), 8.03 (d, J=8.6 Hz, 1H), 8.89 (s, 1H), and 9.33 (d, J=1.9 Hz, 1H).