Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[CH:35]1([CH2:41][CH2:42][NH2:43])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:35]1([CH2:41][CH2:42][NH:43][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][CH:32]=[N:33][C:25]=2[S:24][CH2:23][CH2:22][S:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:20])=[O:21])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: NCCC1CCCCC1
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCC1CCCCC1)c1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
158 mg (0.93 mmol) of CDI were added to a solution of 300 mg (0.93 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (8 ml), and the mixture was stirred for 1 h at RT. A solution of 151 mg (0.93 mmol) of 2-cyclohexylethylamine hydrochloride and 157 μL (0.93 mmol) of diisopropylethyl-amine in DCM (8 ml) was then added, and stirring was continued for a further 16 h at RT. The reaction solution was then washed in each case three times with sat. aq. ammonium chloride solution and saturated aqueous NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. 390 mg (0.90 mmol, 97%) of N-(2-cyclohexylethyl)-2-(2-(phenylsulfonyl)-ethyl-thio)nicotinamide were obtained as residue. MS: m/z 433.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.C(N(CC)CC)C.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:49])=[O:48])[CH:41]=[CH:40]2>CN(C=O)C>[Br:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42]([S:47]([N:50]1[CH2:51][CH2:52][N:53]([C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:15][CH:14]=3)[CH2:54][CH2:55]1)(=[O:48])=[O:49])[CH:41]=[CH:40]2
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2ccccn2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.2 %

Procedure:
4-(2-Pyridyl)benzoic acid (199 mg,1 mmol) was suspended in DMF (5 mL) and triethylamine (0.14 mL, 1 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes then cooled to 5° C. Carbonyl diimidazole (162 mg, 1 mmol) was added and the reaction mixture allowed to warm slowly to room temperature over one hour. 1-(6-Bromonaphth-2-ylsulphonyl)piperazine hydrochloride (393 mg, 1 mmol) was added as a solid in one portion and the reaction mixture was stirred overnight at room temperature then concentrated in vacuo. The crude product was dissolved in ethyl acetate (50 mL) and washed with aqueous sodium bicarbonate solution (2×50 mL). The tube organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting off white solid was subjected to chromatography (SiO2; 100% EtOAc) to yield 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(2-pyridyl)benzoyl]piperazine as a white solid (92 mg); 1H NMR (DMSO-d6) δ=3.09 ppm (s,4H), δ=3.62 ppm (s,4H), δ=7.37 ppm (t,1H), δ=7.51 to 7.99 ppm (m,4H), δ=7.42 and 8.08 ppm (dd,4H), δ=8.17 ppm (dd,2H), δ=8.40 ppm (d,1H), δ=8.47 ppm (s,1H), δ=8.66 ppm (dd,1H); MS (M+H)+ 536.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[CH:20]=2)[C@H:15]([C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[C@H:14]1[C:35]([OH:37])=[O:36].[OH-].[Li+].[CH3:40]COC(C)=O.CCCCCC>>[CH3:40][O:36][C:35]([C@H:14]1[C@H:13]([C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2][OH:1])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[CH:20]=2)[C@@H:15]1[C:26]1[CH:31]=[CH:30][C:29]2[O:32][CH2:33][O:34][C:28]=2[CH:27]=1)=[O:37]
Reactant: CCOC(C)=O
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCCO)[C@H](C(=O)O)[C@H]2c1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCCO)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2

Procedure:
This intermediate was isolated by flash column chromatography (SiO2, EtOAc/Hexane=30/70) of a sample of the crude reaction mixture from the preparation of (1S, 2R, 3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylendioxyphenyl)-5-propoxyindane-2-carboxylic acid described above prior to the saponification with lithium hydroxide.
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].N1C=CC=CC=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)Cl>[S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=1)([O:21][CH2:1][CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4])(=[O:36])=[O:35]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(C)CCCC(C)CCCC(C)CCCC(C)C)cc1
Yield: 138.7 %

Procedure:
Under a nitrogen atmosphere, 29.16 g (97.67 mmol) of phytanol and 9.27 g (117.2 mmol) of pyridine were dissolved in 220 ml of dry methylene chloride, and 20.48 g (107.4 mmol) of p-toluenesulfonyl chloride was added little by little under ice cooling, in order to prevent the liquid temperature from exceeding 10° C. After the completion of addition, agitation was continued for 12 hours until phytanol disappeared, the resulting reaction solution was successively washed with 200 ml of water, 200 ml of 2N hydrochloric acid, and 200 ml of a saturated sodium bicarbonate water, and dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated under reduced pressure to obtain 61.31 g of phytanyl tosylate.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:47]1[N:52]=[C:51]([S:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([F:61])[C:56]=2[F:62])[N:50]=[C:49]([O:63][CH2:64][CH2:65][OH:66])[CH:48]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:62][C:56]1[C:57]([F:61])=[CH:58][CH:59]=[CH:60][C:55]=1[CH2:54][S:53][C:51]1[N:52]=[C:47]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:48]=[C:49]([O:63][CH2:64][CH2:65][OH:66])[N:50]=1
Reactant: CS(N)(=O)=O
Reactant: OCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc(OCCO)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of methanesulfonamide (0.228 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.585 g) and 2-({6-chloro-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl)oxy}ethanol ((the product step i), 0.400 g) in dioxane (20 ml) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 30 mins. The reaction mixture was then reduced in vacuo and the residue separated between DCM (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue was purified by prep HPLC to give the title compound as a white solid. Yield: 102 mg
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:36][CH2:37][CH3:38]>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH:8]([CH2:36][CH2:37][CH3:38])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: CCCI
Reactant: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccccc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 28.3 %

Procedure:
A solution of methyl 2-(4-methyl-6-phenyl-2-(piperidin-1-yl)pyrimidin-5-yl)acetate (150 mg; 0.461 mmol) in dry DMF (2.5 mL) was cooled to −15° C. LHMDS (0.507 mL; 0.507 mmol; 1M in THF) was added dropwise and the mixture was stirred at −15° C. for 15 min followed by the dropwise addition of iodopropane (0.068 mL; 0.691 mmol), After stirring for 2 h at −15° C. the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-10%) in heptane to give 48 mg (28%) of the title compound as a yellow oil. ESI/APCI(+): 368 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:5]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=[C:4]2[N:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:5]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=[C:4]2[N:3]=1
Reactant: Cc1ccc(-c2c(CO)c(C)nc3cc(-c4ccccc4)nn23)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1ccc(-c2c(C=O)c(C)nc3cc(-c4ccccc4)nn23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
To a stirred solution of (5-methyl-2-phenyl-7-p-tolylpyrazolo[1,5-a]pyrimidin-6-yl)methanol (100 mg, 0.304 mmol) in CH2Cl2 (8 mL) was added PCC (98 mg, 0.455 mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue was purified by silica gel chromatography to give the title compound (82 mg, 83%). 1H-NMR (500 MHz, CDCl3) δ ppm 2.52 (3H, s), 2.89 (3H, s), 6.98 (1H, s), 7.33-7.50 (5H, m), 7.60 (2H, d, J=7.9 Hz), 7.91 (2H, dd, J=8.1, 1.4 Hz), 9.80 (1H, s).
Reaction SMILES: [C:1]([C:3]1[CH2:9][CH:8]2[N:10]([CH2:11][CH:12]([F:14])[F:13])[CH:5]([CH2:6][CH2:7]2)[CH:4]=1)#[N:2].CO.[BH4-].[Na+].P([O-])(O)(O)=O.[K+]>N1C=CC=CC=1>[C:1]([CH:3]1[CH2:4][CH:5]2[N:10]([CH2:11][CH:12]([F:14])[F:13])[CH:8]([CH2:7][CH2:6]2)[CH2:9]1)#[N:2]
Reactant: N#CC1=CC2CCC(C1)N2CC(F)F
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: c1ccncc1
Product: N#CC1CC2CCC(C1)N2CC(F)F
Yield: 185637.09 %

Procedure:
An oven-dried 10 ml round bottom flask was fitted with a reflux condenser and a magnetic stirrer and placed under an atmosphere of nitrogen. 3-Cyano-8-(2,2-difluoroethyl)-8-azabicyclo[3.2.1]oct-2-ene (0.17 g, 0.53 mmol) was charged to the reactor followed by methanol (0.25 ml) and pyridine (0.75 ml) to give a solution. Solid sodium borohydride (0.039 g, 1.03 mmol) was added in a single portion and the mixture was then heated and held at reflux for 3 hour. After cooling to ambient, the reaction mass was poured into an agitated saturated aqueous potassium dihydrogen phosphate (10 ml) solution. The aqueous solution was extracted with dichloromethane (3×10 ml) and the combined organic layers were dried (Na2SO4). Concentration in vacuo to give 3-cyano-8-(2,2-difluoroethyl)-8-azabicyclo-[3.2.1]octane(0. 197 g, 95% yield) as a mixture of epimers (90:10 exo:endo).
Reaction SMILES: [C:1]([O:10][CH2:11][Cl:12])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:13]C1C=CC(CC(O)=O)=CC=1.C(=O)([O-])O.[Na+].ClCOS(Cl)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl.ClCCl>[CH3:13][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][C:1]([O:10][CH2:11][Cl:12])=[O:9])=[CH:4][CH:5]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: CCCCCCCC(=O)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)(Cl)OCCl
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(CC(=O)OCCl)cc1
Reaction time: 18 h
Yield: 80 %

Procedure:
A similar procedure (Harada, N. et al. Synth. Commun. 1995, 25, 767-772) to that described for the preparation of 43 was followed using 4-methylphenylacetic acid (2.27 g, 15.15 mmol), sodium hydrogen carbonate (5.09 g, 60.6 mmol) and tetra-n-butylammonium hydrogen sulfate (0.51 g, 1.52 mmol) in water-dichloromethane (62.5 mL, 1:1 v/v) and chloromethylchlorosulfate (2.50 g, 15.15 mmol) in dichloromethane (7.5 mL), at room temperature for 18 h. Purification by flash chromatography (hexane/ethyl acetate 9:1) afforded 322 as a colourless oil (2.42 g, 12.18 mmol, 80%).
Reaction SMILES: Cl[C:2](=[CH2:12])[CH2:3][CH:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[OH:5].[OH-].[Na+].Cl>CN(C)C=O>[CH2:6]([CH:4]([CH2:3][C:2]#[CH:12])[OH:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=C(Cl)CC(O)CCCCCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C#CCC(O)CCCCCC
Yield: 97 %

Procedure:
20.00 Grams of the 2-chloroallyl-n-hexylcarbinol obtained above were dissolved in 200 g of N,N-dimethylformamide, and 8.39 g of sodium hydroxide in a flake form were added. The resultant mixture was stirred at 25° C. for 10 hours. After the reaction was completed the reaction mixture was neutralized with concentrated hydrochloric acid, and insolubles were filtered off. After the filtrate was concentrated under reduced pressure, the concentration residue was subjected to extraction with toluene, washed with a 7% sodium carbonate aqueous solution and then dried over sodium sulfate. The desiccant was filtered off, and the toluene was distilled off. The resultant oily substance was distilled under reduced pressure to give 15.70 g of n-hexylpropargylcarbinol. The results were as follows.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[S:12][C:11]([C:13](=[O:15])[CH3:14])=[CH:10][C:9]=1[CH3:16].C(N(CC)CC)C>CN(C=O)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.[Cu]I>[CH3:16][C:9]1[CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[S:12][C:8]=1[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)c1cc(C)c(Br)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(C)c(C#C[Si](C)(C)C)s1
Reaction time: 3 h

Procedure:
Trimethylsilylacetylene (16 ml) is added to a solution of 1-(5-bromo-4-methyl-thiophen-2-yl)-ethanone (16.9 q, example 1, step A), Pd(PPh3)2Cl2 (3.78 g), CuI (1.46 g) and triethylamine (16 ml) in DMF (15 ml). After 3 hours at room temperature, the reaction is quenched with water and extracted three times with ethyl acetate. The organic phases are combined, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by filtration over a plug of silica gel eluting with dichloromethane to yield 1-(4-methyl-5-trimethylsilanylethynyl-thiophen-2-yl)-ethanone (18.2 g) as yellow solid. The compound is used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:14][CH:10]([F:15])[O:8][C:7]1[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccnc1Br
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1cccnc1Br
Temperature: 100 °C
Yield: 35.2 %

Procedure:
To a solution of 2-bromo-3-pyridinol (1.26 g, 7.23 mmol) in DMF (35 mL) and water (5 mL) was added sodium chlorodifluoroacetate (2.93 g, 18.1 mmol) followed by cesium carbonate (4.71 g, 14.5 mmol). The reaction was heated to 100° C. for 36 hours before partitioning between EtOAc and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EtOAc:Heptane 1:3 to afford the title compound as a colourless oil (570 mg, 35%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13](OC)=[O:14])[N+:9]([O-:17])=[C:8]([NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:7]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(Cl)Cl.[OH-].[Na+]>O>[N:1]1([C:6]2[CH:7]=[C:8]([NH:18][C:19]([O:21][CH3:22])=[O:20])[N:9]3[O:17][C:13](=[O:14])[N:12]=[C:10]3[N:11]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: COC(=O)Nc1cc(N2CC=CC2)nc(NC(=O)OC)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1cc(N2CC=CC2)nc2nc(=O)on12
Reaction time: 3 h

Procedure:
4.5 G. of dimethyl 6-(3-pyrrolin-1-yl)-2,4-pyrimidine-dicarbamate-3-oxide are suspended in a mixture of 200 ml. of methylene chloride and 200 ml. of water. The suspension is adjusted with concentrated sodium hydroxide to pH 12.5 and stirred at this pH for 3 hours. The two phases are then separated and the aqueous phase is adjusted to pH 3 with concentrated hydrochloric acid. The separated white precipitate is filtered off, pre-dried and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure methyl 5-(3-pyrrolin-1-yl)-2-oxo-2H-[1,2,4]-oxadiazolo[2,3-a]pyrimidine-7-carbamate, having a melting point of 230°-234° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH:9](Cl)[CH3:10])=[CH:5][N:4]=1.[CH3:14][S-:15].[Na+]>C(O)C>[Cl:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([S:15][CH3:14])[CH3:10])=[CH:5][N:4]=1
Reactant: CC(Cl)c1ccc(C(F)(F)Cl)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSC(C)c1ccc(C(F)(F)Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
To a solution of 2-[chloro(difluoro)methyl]-5-(1-chloroethyl)pyridine (D) (0.81 g, 3.6 mmol) in ethanol (10 mL) was added sodium thiomethoxide (0.52 g, 7.4 mmol) under stirring in one portion at 0° C. After 10 min, the mixture was allowed to warm to room temperature and stirred overnight. The solvent ethanol was then removed under reduced pressure and the residue was re-taken into ether/CH2Cl2 and brine. The two phases were separated and the organic layer was extracted with CH2Cl2 one more time. The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, purified on silica gel using 5 percent ethyl acetate in hexane to give 0.348 g of the 2-[chloro(difluoro)methyl]-5-[1-(methylthio)ethyl]pyridine (E) in 40 percent yield GC-MS: mass calcd for C9H10ClF2NS [M]+ 237. Found 237.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([O:13][CH2:14][C@H:15]2[CH2:19][CH2:18][CH2:17][NH:16]2)[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=1.[F:20][C:21]([F:32])([F:31])[C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[Cl:3][C:4]1[CH:5]=[C:6]([O:13][CH2:14][C@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:28]([C@H:25]2[CH2:24][CH2:23][C@H:22]([C:21]([F:20])([F:31])[F:32])[CH2:27][CH2:26]2)=[O:29])[C:7]([C:10]([NH2:12])=[O:11])=[N:8][CH:9]=1
Reactant: NC(=O)c1ncc(Cl)cc1OC[C@H]1CCCN1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: Cl
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: NC(=O)c1ncc(Cl)cc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 3 using (R)-5-chloro-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride (EXAMPLE 29 Step 5) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.[CH2:10]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][CH3:14].Cl>C(NCC)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.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:22]#[C:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:16][CH:17]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: C#Cc1ccc(CCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: CCCCCc1ccc(C#Cc2ccc(Br)cc2F)cc1
Temperature: 5 °C
Yield: 41.3 %

Procedure:
4-Bromo-2-fluoro-1-iodobenzene (57 g) was dissolved in diethylamine (66 ml) under nitrogen atmosphere, and then bis(triphenylphosphine)palladium(II) chloride (0.5 g) and copper(I) iodide (0.5 g) were added thereto, followed by stirring. The flask was cooled to 5° C. or lower, and then 4-pentylphenylacetylene (36 g) was added dropwise thereto. After stirring at room temperature for 5 hours, the reaction solution was poured into a mixture of concentrated hydrochloric acid (40 ml) and ice (30 g). After extraction with chloroform, the resultant was washed twice with water, followed by distilling off chloroform therefrom. The residue was distilled under reduced pressure (b.p. 205° to 210° C./3 mmHg), and then recrystallized from a mixed solvent of acetone and methanol to give 4-bromo-2-fluoro-4'-pentyltolane (27 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([CH2:17]O)=[CH:10][C:9]=1[O:19][CH3:20].P(Br)(Br)[Br:23]>C1COCC1>[Br:23][CH2:17][C:11]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:21])=[C:9]([O:19][CH3:20])[CH:10]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(CO)cc1OC
Solvent: C1CCOC1
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(CBr)cc1OC

Procedure:
To a solution of methyl 4-[4′-(hydroxymethyl)-2′-methoxy-5′-nitrophenoxy]butanoate (6) (750 mg, 2.52 mmol) in anhydrous THF (10 cm3) was added PBr3 (0.24 cm3, 2.52 mmol). The resulting deep yellow solution was refluxed for 3 hours, after which time no visible changes had occurred. The reaction mixture was cooled then poured onto ice. The resulting aqueous solution was extracted with ether (3×30 cm3). The combined organic extracts were washed with 5% NaHCO3 solution (2×30 cm3) and water (2×30 cm3) before being dried (MgSO4) and concentrated in vacuo. The desired compound 7 was furnished as a yellow oil. The oil was then purified via column chromatography (SiO2, hexane:EtOAc, 2:1 v/v) thus providing 7 as a yellow powder (580 mg, 64%). m.p. 68–70° C.; Found C, 43.2; H, 4.5; N, 4.0; Br, 21.9; C13H16NO6Br requires C, 43.1; H, 4.4; N, 3.9; Br, 22.1%; Rf 0.63 (SiO2, hexane:EtOAc 2:1 v/v); νmax (KBr disc)/cm−1 3000–2800 (m), 1720 (s), 1610, 1580, 1530, 1280, 1220; δH (200 MHz, CDCl3) 2.20 (2H, q, J 6.7 Hz, CH2), 2.56 (2H, t, J 6.7 Hz, CH2), 3.70 (3H, s, OCH3), 3.97 (3H, s, OCH3), 4.13 (2H, t, J 6.7 Hz, CH2), 4.86 (2H, s, CH2), 6.92 (1H, s, H-3′), 7.67 (1H, s, H-6′) ppm; δc (100 MHz, CDCl3) 24.1 (CH2), 30.1 (CH2), 51.6 (OCH3), 56.4 (OCH3), 68.0 (CH2), 68.3 (CH2), 109,7 (CH), 113.8 (CH), 127.3, 140.0, 148.1, 153.5, 173.2 (COOCH3) ppm; m/z (FAB) 362 [(MH+), 100%].