Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:17](=[O:35])[N:18]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=2)[CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:21]=1)#[N:9].[OH-].[Na+].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:17](=[O:35])[N:18]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][S:39]([CH3:38])(=[O:41])=[O:40])[CH:29]=2)[CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:21]=1)#[N:9]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(N)c2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(-n2cc(-c3ccccn3)cc(-c3ccccc3C#N)c2=O)c1
Reaction time: 0.17 h

Procedure:
Triethylamine (0.2 ml) was added to a solution of 31 mg of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-aminophenyl)-1,2-dihydropyridin-2-one in 2 ml of tetrahydrofuran, 0.1 ml of methanesulfonic acid chloride was dropped thereinto with ice cooling and the mixture was stirred for 10 minutes. To this were added 2 ml of 2N sodium hydroxide, the mixture was stirred at room temperature for 5 minutes and partitioned to ethyl acetate-water, the organic layer was washed with water, dried and concentrated and the residue was purified by a silica gel column chromatography (ethyl acetate-hexane system) to give 38 mg of the title compound as a pale yellow amorphous substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([C:22](=O)[CH2:23][CH2:24][C:25](OCC)=[O:26])=[CH:17][C:16]=2[F:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:33][NH2:34]>C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([C:22]3[CH2:23][CH2:24][C:25](=[O:26])[NH:34][N:33]=3)=[CH:17][C:16]=2[F:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)CCC(=O)c1cc(F)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc(C3=NNC(=O)CC3)cc2F)CC1
Yield: 14.1 %

Procedure:
A mixture of 4-[4-(3-ethoxycarbonyl-propionyl)-2,6-difluoro-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (3.21 g, 7.27 mmol) and hydrazine monohydrate (0.7 mL, 14.1 mmol) in isopropanol (20 mL) was stirred at reflux overnight. Isopropanol was concentrated at reduced pressure and partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude material. The crude material was purified by ISCO (80 g silica gel column) chromatography using 15 to 60% EtOAc in hexane to obtain 4-[2,6-difluoro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (0.42 g, 14%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([NH:14][C:15](=[O:17])[CH3:16])[C:8]=2[N:7]=[C:6]1[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25].[CH3:31]I.[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N:14]([CH3:31])[C:15](=[O:17])[CH3:16])[C:8]=2[N:7]=[C:6]1[C:18]1[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=1[F:24]
Reactant: CC(=O)Nc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetamidobenzimidazole (Example 88) (2.44 g, 5.90 mmol) and methyl iodide (0.60 mL, 9.69 mmol) dissolved in THF (30 mL) was added excess NaH. After stirring overnight, the solution was concentrated to dryness, diluted with CH2Cl2, and washed with water, NaHSO4(10% soln) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol in CH2Cl2, yielding 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N-methylacetamido)-benzimidazole (0.89 g, 2.08 mmol, 63% yield). M.p. 155-156° C. 1H NMR (200 MHz, CD2Cl2): δ 7.55 (m, 1H, H4′), 7.48 (br d, J=7.4 Hz, 1H, H5), 7.31 (dd, J=7.4, 7.7 Hz, 1H, H6), 7.27 (m, 1H, H4″), 7.14 (dd , J=1.1, 7.7 Hz, 1H, H7), 7.09 (m, 2H, H3′,5′), 6.84 (m, 2H, H3″,5″), 5.38 (s, 2H, CH2PhF2), 3.34 (s, 3H, NCH3), 1.83 (s, 3H, NAc).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](C)=[N:9]2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[C@H:20]([OH:23])[CH2:21][OH:22].Cl[C:25]1C=CC(C2C(C=C)=C(C)C=C3C=2C=CC=N3)=CC=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:4]2[C:3]([C@H:20]([OH:23])[CH2:21][OH:22])=[C:2]([CH3:25])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:18][CH:17]=1
Reactant: C=Cc1c(C)cc2ncccc2c1-c1ccc(Cl)cc1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@H](O)CO)c(Cl)cc2n1
Product: Cc1cc2ncccc2c(-c2ccc(Cl)cc2)c1[C@H](O)CO

Procedure:
Compound 3H was prepared following the procedure used to prepare compound 1H of Example 1, except that 5-(4-chlorophenyl)-7-methyl-6-vinyl-quinoline (3G) was used instead of compound 1G. LCMS-ESI+ (m/z): 314.2, 316.2 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH2:13])=[N:2]1.C(N(C(C)C)CC)(C)C.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([Cl:23])=[CH:25][CH:26]=2)=[N:2]1
Reactant: NCCNc1nsc2ccccc12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCNc1nsc2ccccc12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N1-(Benzo [d]isothiazol-3-yl)ethane-1,2-diamine (50 mg, 0.26 mmol) was dissolved in anhydrous dichloromethane (5 mL) with diisopropylethylamine (50 μL, 0.28 mmol). The solution was cooled on an ice-water bath and then a solution of 4-chlorobenzoyl chloride (36 μL, 0.28 mmol) in dichloromethane (0.5 mL) was added dropwise. The reaction mixture was allowed to stir for 2 h while warming to room temperature. The solution was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 25% ethyl acetate in hexanes, and selected fractions were combined and concentrated under reduced pressure to yield N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-4-chlorobenzamide as a white solid, (50 mg). 1H NMR (300 MHz, DMSO-d6): 8.7 (broad s, 1H), 8.1 (d, 1H), 7.9 (m, 3H), 7.5 (m, 4H), 7.4 (m, 1H), 3.6 ppm (m, 4H). MW=332 confirmed by LC-MS, tr=3.89 min (Method B) MH+=333.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][C:38]([S:42](Cl)(=[O:44])=[O:43])=[CH:39][CH:40]=2)[CH:35]=[CH:34]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:42]([C:38]1[CH:37]=[C:36]2[C:41](=[CH:40][CH:39]=1)[N:33]([CH3:32])[CH:34]=[CH:35]2)(=[O:43])=[O:44]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: Cn1ccc2cc(S(=O)(=O)Cl)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1ccc2cc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5c4ncn5C4CCCCO4)c3F)ccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 1-methyl-1H-indole-5-sulfonyl chloride (16 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:9][CH:8]([C:10]2[CH:31]=[CH:30][C:13]3[C:14]4[N:15]=[C:16]([C:22]5[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][N:26]=5)[S:17][C:18]=4[CH2:19][CH2:20][O:21][C:12]=3[CH:11]=2)[CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[CH3:32][NH:33][CH3:34]>>[CH:27]([N:23]1[C:22]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:12]4[CH:11]=[C:10]([CH:8]5[CH2:7][N:6]([S:3]([CH2:1][CH2:2][N:33]([CH3:34])[CH3:32])(=[O:5])=[O:4])[CH2:9]5)[CH:31]=[CH:30][C:13]=4[C:14]=3[N:15]=2)=[N:26][CH:25]=[N:24]1)([CH3:28])[CH3:29]
Reactant: C=CS(=O)(=O)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Reactant: CNC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(S(=O)(=O)CCN(C)C)C3)ccc1-2
Reaction time: 72 h
Yield: 50.3 %

Procedure:
To a suspension of 8-(1-ethenesulfonyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (75 mg, 0.17 mmol) in IMS (2 mL) was added dimethylamine (2M in MeOH, 158 μL, 0.32 mmol) and the reaction mixture was stirred for 72 hours. The mixture was concentrated in vacuo to low volume and partitioned between DCM and water. The layers were separated and the organic layer was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was combined with a previous batch of the desired compound and purified by flash chromatography (SiO2, 0-2% MeOH in DCM) to give 455 as a white solid (43 mg, 34%). LCMS: RT=8.51 min, [M+H]+=503. 1H NMR δ (ppm) (CDCl3): 8.36 (1 H, d, J=8.20 Hz), 7.90 (1 H, s), 7.16 (1 H, dd, J=8.24, 1.92 Hz), 7.03 (1 H, d, J=1.88 Hz), 5.93-5.83 (1 H, m), 4.39 (2 H, t, J=5.04 Hz), 4.26 (2 H, t, J=8.23 Hz), 4.10 (2 H, t, J=7.33 Hz), 3.81-3.74 (1 H, m), 3.40 (2H, t, J=5.05 Hz), 3.22-3.14 (2 H, m), 2.81 (2H, t, J=7.47 Hz), 2.29 (6 H, s), 1.61 (6 H, d, J=6.63 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([CH3:24])[N:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:21]3[CH:22]=[C:17]([Cl:16])[N:18]=[C:19]([CH3:24])[N:20]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2cc(O)ccc12
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cccc2cc(Oc3cc(Cl)nc(C)n3)ccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A suspension of 6.0 g (29.7 mMol) 6-hydroxy-naphthalene-1-carboxylic acid methyl ester (see Step 3.1), 7.6 g (46.6 mMol) 4,6-dichloro-2-methylpyrimidine and 13.9 g (65 mMol) K3PO4 in 50 ml NMP is stirred for 4 days at rt. The mixture is poured into ½ l water and the title compound filtered off, washed with water and dried (HV, 80° C.): HPLC: tRet=17.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([N+:20]([O-])=O)=[C:14]([CH:19]=2)[C:15]([NH:17][CH3:18])=[O:16])[CH2:6][CH2:5]1>CO.CO.C(Cl)Cl>[NH2:20][C:13]1[CH:12]=[CH:11][C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16]
Reactant: CNC(=O)c1cc(N2CCN(CCO)CC2)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1cc(N2CCN(CCO)CC2)ccc1N

Procedure:
A solution of 5-[4-(2-hydroxyethyl)-1-piperazinyl]-N-methyl-2-nitrobenzamide 3 in 250 mL of MeOH in a 250 mL round botton flask was stirred at room temperature under hydrogen balloon over night. The resulted mixture was filtered to get rid of the Pd catalyst. TLC in 10% MeOH/CH2Cl2 showed no more starting material and a major product. The solvent was rotavaped to dryness, and the residue was used without further purification. MS (ES) m/e 279 [M+H].
Reaction SMILES: CSC.C([O:11][C@@H:12]1[C@H:17]([O:18]CC2C=CC=CC=2)[C@H:16]([O:26]CC2C=CC=CC=2)[CH:15]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[C:36]([CH2:44][C:45]3[S:49][C:48]4[CH:50]=[CH:51][C:52]([O:54][CH3:55])=[CH:53][C:47]=4[CH:46]=3)[CH:35]=2)[O:14][C@@H:13]1[CH2:56][O:57]CC1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:57][CH2:56][C@@H:13]1[C@@H:12]([OH:11])[C@H:17]([OH:18])[C@@H:16]([OH:26])[C@H:15]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[C:36]([CH2:44][C:45]3[S:49][C:48]4[CH:50]=[CH:51][C:52]([O:54][CH3:55])=[CH:53][C:47]=4[CH:46]=3)[CH:35]=2)[O:14]1
Reactant: COc1ccc2sc(Cc3cc(C4O[C@H](COCc5ccccc5)[C@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@@H]4OCc4ccccc4)c4ccccc4c3)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSC
Solvent: ClCCl
Product: COc1ccc2sc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c4ccccc4c3)cc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.5 %

Procedure:
Under a nitrogen atmosphere, dimethylsulfide (0.66 ml) and a boron trifluoride-diethyl ether complex (0.33 ml, 2.62 mmol) were added to a solution of (2R,3S,4R,5R)-3,4,5-trisbenzyloxy-2-benzyloxymethyl-6-[3-(5-methoxybenzo-[b]thiophen-2-ylmethyl)-naphthalen-1-yl]tetrahydropyran (217 ml, 0.262 mmol) in methylene chloride (4 ml) under cooling with ice. The reaction mixture was stirred at room temperature for three days, and then a saturated sodium hydrogen carbonate aqueous solution was added under cooling with ice and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried with sodium sulfate, and then the solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=methylene chloride:methanol (30:1)] to obtain the title compound (85 mg, 65%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:18][C:17]=2[CH3:25])=[CH:12][CH:11]=1.C(OCC)(=O)C>C1COCC1>[Br:1][C:18]1[C:17]([CH3:25])=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=2)[NH:20][C:19]=1[C:21](=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)c1cc(C)c(-c2ccc(Cl)cc2)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)c1[nH]c(-c2ccc(Cl)cc2)c(C)c1Br
Temperature: -78 °C
Reaction time: 5 h
Yield: 76.8 %

Procedure:
A solution of N-bromosuccinimide (1.25 g, 7.06 mmol) in THF (20 ml) was added dropwise to a stirred solution of 1-(5-(4-chlorophenyl)-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 53a, 1.75 g, 7.06 mmol) in THF (40 ml) at about −78° C. The resulting reaction mixture was stirred at about −78° C. for 5 hr. The reaction mixture was then allowed to warm to 25° C. slowly during further 3 to 4 hr. The progress of the reaction was monitored by TLC. The solvent was evaporated from the reaction mixture under reduced pressure and to the residue so obtained was added ethyl acetate (200 ml). The mixture so obtained was washed with saturated sodium bicarbonate solution (1×50 ml) followed by washing with water (1×50 ml). The combined organic layer was then dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 10 ethyl acetate in hexanes to obtain the title compound (1.77 g, 77%)
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[CH:11]1[C:24]2NC3C(=CC=CC=3)SC=2C=C[CH:12]=1.C(Cl)C=C>[Co]>[CH2:9]([O:8][P:1]([CH2:24][CH:11]=[CH2:12])(=[O:2])[O:5][CH2:6][CH3:7])[CH3:10]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: CCOP(OCC)OCC
Agent: [Co]
Solvent: C=CCCl
Product: C=CCP(=O)(OCC)OCC
Reaction time: 5.5 h

Procedure:
166 parts of triethyl phosphite are heated for 1 hour to 140° C in a nitrogen atmosphere with 2 parts of highly active Raney cobalt (Ra-Co-Lu). A mixture of 1 part of phenothiazine and 80 parts of allyl chloride is then added dropwise at 140° C. Once the reaction has started, the temperature may be lowered to 120° C. After 5.5 hours, 63 parts of ethyl chloride have distilled off and the mixture is deep blue in colour. Fractional distillation gives 135 parts of allyl phosphonic acid diethyl ester, corresponding to 76% of the theoretical yield.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:29]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:31])[CH3:30].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[C:13]([O:12][C:10]([NH:1][C@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7](=[O:9])[CH2:30][C:29]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC[C@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(=O)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of Boc-D-alloIle-OH (15.26 g, 65.9 mmol) in dry THF (200 ml) at 0° C. under argon, was added CDI (16.04 g, 98.96 mmol). After 15 min, the mixture was allowed to warm to room temperature, and stirred over a period of 16 h. The resulting solution was cooled to −78° C., and added via cannula to a well stirred solution of benzyl lithium enolate cooled at −78° C. (625 ml, 0.37 M), [prepared by adding dropwise a solution of benzyl acetate (33.34 ml), in THF (165 ml) to a solution of lithium diisopropylamide (0.36M) in THF/hex 3:1 (642 ml) at −78° C.]. The temperature should be kept <−75° C. The reaction mixture was stirred at −78° C. for 60 min. Then, it was allowed to come to −10° C. (30 min), recooled to −78° C. and quenched with saturated aq. ammonium chloride (200 ml), then extracted with DCM (3×500 ml) at room temperature. The combined extracts were washed successively with aq sat. NaHCO3 (500 ml) and brine (200 ml). Drying (Na2SO4) followed by removal of solvent gave an oil, which was coated on silica C18 and loaded to the top of a LC-RPC18 [Lichroprep RPC-18 (40-60 microns) column. Elution using a gradient ACN-H2O (60 to 100% ACN)] yielded the product C4 as a colourless oil (16.7 g, 70%). [α]20D −20.0 (c 1, CHCl3), TLC: Rf=0.32 (Merck, RP-C18, ACN-H2O 7:3).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[C:1]([O:5][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH3:6])(=[O:4])[C:2]#[CH:3]
Reactant: COCCOCCO
Reactant: C#CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C#CC(=O)OCCOCCOC

Procedure:
12.3 ml (0.2 mol) of propiolic acid are heated at reflux for 20 hours together with 23.6 ml (0.2 mol) of diethylene glycol monomethyl ether, 1.5 g (8 mmol) of p-toluenesulphonic acid monohydrate and 80 ml of toluene, and the resulting reaction water was distilled off azeotropically and collected in a water separator. After completion of the water separation the reaction mixture was washed in succession with saturated sodium bicarbonate solution and with water. The toluene phase was dried over sodium sulphate and concentrated. The crude product was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained 2-(2-methoxyethoxy)ethyl propiolate as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:5]([S:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:4]=1)#N.C(O)=[O:24]>[Ni]>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[S:14][C:5]1[CH:4]=[C:3]([CH:1]=[O:24])[CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1Sc1ccc(F)cc1F
Reactant: O=CO
Agent: [Ni]
Product: CS(=O)(=O)Nc1ccc(C=O)cc1Sc1ccc(F)cc1F

Procedure:
A mixture of 4'-cyano-2'-(2,4-difluorophenylthio)methanesulfonanilide (4.8 g) and Raney's Nickel (4.8 g) in 75% formic acid (130 ml) was stirred and refluxed for 2 hours. The mixture was filtered and the filtrate was concentrated to dryness. The residue was dissolved in chloroform, washed with an aqueous solution of sodium bicarbonate, dried and evaporated. The oily residue (5 g) was purified by column chromatography on silica gel (100 g) eluting with a mixture of toluene and ethyl acetate (5:1) to give crystals of 2'-(2,4-difluorophenylthio)-4'-formylmethanesulfonanilide (3.0 g).
Reaction SMILES: CS([O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:7])(=O)=O.[CH:21]1[C:22]([I:30])=[CH:23][C:24]([I:29])=[C:25](O)[C:26]=1[I:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:27][C:26]1[CH:25]=[C:24]([I:29])[CH:23]=[C:22]([I:30])[C:21]=1[O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:7]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: CCCCCCCCCCCCCC(C)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCC(C)Oc1c(I)cc(I)cc1I
Temperature: 85 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
To a solution of 2-methanesulfonyloxypentadecane (15.5 g, 48.1 mmol) in dry DMF (200 ml) was added triiodophenol (22.6 g, 47.9 mmol) and potassium carbonate (6.6 g, 47.8 mmol). The reaction flask was immersed in an oil bath which was heated to 85° C. over a period of 0.5 hr. The reaction was stirred under N2 atmosphere for 16 hrs. At the end of this period the reaction was processed as for Example 1 except at 4 times the volumes to provide a brown residue. Flash column chromatography (silica, hexanes) provided 2-(2,4,6-triiodophenoxy)pentadecane (19.2 g, 58.8%) as a white solid. Mp: 56°-58° C. p Title Compound:1H (300 MHz) and 13C (75 MHz) NMR spectra were consistent with the desired structure. Calculated for C21H33I3O: C, 36.97; H, 4.88; I, 55.81. Found: C, 36.89, H, 4.80; I, 55.85.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH:7]=[CH:6][C:5]2=[O:14].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[NH:15]([C:7]1[C:8](=[O:13])[C:9]2[C:4]([C:5](=[O:14])[CH:6]=1)=[CH:3][C:2]([CH3:1])=[C:11]([CH3:12])[CH:10]=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: Cc1cc2c(cc1C)C(=O)C=CC2=O
Solvent: CCO
Product: Cc1cc2c(cc1C)C(=O)C(Nc1ccccc1)=CC2=O
Reaction time: 8 h
Yield: 34 %

Procedure:
To a warm solution of 6,7-dimethyl-1,4-naphthoquinone (1.08g; 0.058 mole) in ethanol (20ml) was added aniline (0.5ml) and the red solution refluxed for 1 hr. on a steam bath. After standing overnight the red crystalline anilino derivative was filtered off and recrystallised from acetic acid; water to give 0.54g (34%) of material of m.p. 208°-210° C. (Found C, 78.02; H, 5,47; N, 4.88; C18H15NO2 requires; C, 77.96; H, 5.45; N, 5.05%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([N:15](C(OC(C)(C)C)=O)[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:13][CH:14]=1>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:13][CH:14]=1
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNc1ccc(Br)cn1
Reaction time: 0.75 h
Yield: 100.4 %

Procedure:
A 50% solution of TFA in CH2Cl2 (200 mL) was added to 5-bromo-[N-(tert-butoxycarbonyl)-N-(methoxycarbonylmethyl)amino]pyridine (16.5 g, 46 mmole). After stirring for 45 min the reaction was concentrated to dryness, and the residue was diluted with 1.0 N Na2CO3 (300 mL). The mixture was extracted with EtOAc (300 mL), and the organic layer was washed with brine, dried (Na2SO4), and concentrated to dryness under vacuum. The title compound (11.32 g, 100%) was obtained as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=2.3 Hz, 1 H), 7.48 (dd, 1 H), 6.40 (d, J=8.8 Hz, 1 H), 4.95 (br s, 1H), 4.12 (d, J=5.5 Hz, 2 H), 3.78 (s, 3H).