Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:22]#[N:23])=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(c2ccc(I)cc2)COC1(C)C
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1C(c2ccc(C#N)cc2)COC1(C)C
Yield: 55 %

Procedure:
A stirred solution of (RS)-4-(4-iodo-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (200 mg, example 1(e)), zinc cyanide (66 mg) and tetrakis(triphenyl-phosphine)palladium (57 mg) in DMF (4 ml) under an argon atmosphere in a sealed tube was heated at 160° C. for 15 minutes under microwave irradiation. The mixture was then poured onto ice-water and the mixture extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (RS)-4-(4-cyano-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (82 mg, 55%) as a colourless viscous oil. MS (ISP): 325.4 ([M+Na]+), 303.4 ([M+H]+), 247.3 ([M+H—C4H8]+).
Reaction SMILES: [SH:1][C:2]1[NH:6][N:5]=[N:4][CH:3]=1.I[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]I>C(O)C>[N:4]1[CH:3]=[C:2]([S:1][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:1][C:2]2[NH:6][N:5]=[N:4][CH:3]=2)[NH:6][N:5]=1
Reactant: Sc1cnn[nH]1
Reactant: ICCCCCCCCI
Solvent: CCO
Product: c1nn[nH]c1SCCCCCCCCSc1cnn[nH]1
Yield: 41.6 %

Procedure:
20 mmole of 5-mercapto-1H-1,2,3-triazole (sodium salt) was dissolved in 20 ml of ethanol in stirring. 10 mmole of 1,8-diiodooctane was added dropwise to the solution of 5-mercapto-1H-1,2,3-triazole (sodium salt), and stirred overnight. After the solvent was evaporated in vacuum, the residual was washed with 50 ml pure H2O for three times, and then with 50 ml hexane for 3 times. At last, the residual was dried in oven at 60° C. for 24 hours. 1.30 g product was obtained as white solid. Yield: 42%. 1H NMR (DMSO): δ (ppm) 7.88 (2H, s), 2.86 (4H, t, JH-H=7.14), 1.50 (4H, m), and 1.20-1.31 (8H, m).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1>CO.O.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[CH:11][C:10]=1[O:30][CH3:31]
Reactant: COc1cc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COc1cc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)ccc1O
Reaction time: 1 h
Yield: 46.5 %

Procedure:
A solution of compound (1R,2R)-1-{2-[2-(4-benzyloxy-3-methoxyphenyl)ethoxy]cyclohexyl}-(3R)-pyrrolidin-3-ol (50.3 g, 100 mmol) in methanol (250 mL) was transferred to a Parr shaker bottle that has previously been charged with Pd/C (10% wt/wt, 4.0 g) as a slurry in water. The bottle was placed on a Parr hydrogenator and evacuated. Hydrogen pressure (60 psi) was then applied and the vessel was shaken for 1 hour. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was dissolved in water (250 mL) and washed successively with ethyl acetate (3×200 mL) and chloroform (10×150 mL). The aqueous solution was saturated with NaCl and washed with dichloromethane (4×200 mL). The combined organic extract was concentrated and 5% aqueous NaHCO3 (200 mL) was added to the residue. The suspension was stirred for 30 minutes and then extracted with ethyl acetate (8×250 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford a yellowish powder. The powder was then triturated with ethyl acetate (3×50 mL) and subjected to high vacuum (oil pump) to afford (3R)-1-[(1R,2R)-2-[2-(4-hydroxy-3-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (15.6 g, 43% yield) as a white powder; 1H NMR (400 MHz, CDCl3) δ 6.82 (d, 1H, J=8.0), 6.75 (br s, 1H), 6.70 (d, 1H, J=8.0), 4.30-4.20 (m, 1H), 3.87 (s, 3H), 3.78-3.70 (m, 1H), 3.56 (q, 1H), 3.33 (td, 1H, J=7.6, J=3.6), 2.97-2.89 (m, 1H), 2.84-2.75 (m, 3H), 2.65 (dd, 1H, J=10, J=5.2), 2.55-2.38 (m, 2H), 2.09-1.95 (m, 2H), 1.91-1.82 (m, 1H), 1.73-1.58 (m, 3H), 1.41-1.15 (m, 4H); 13C-NMR (100 MHz, CDCl3) δ 23.25, 23.68, 27.59, 29.21, 34.42, 36.70, 48.84, 56.06, 59.93, 63.68, 69.83, 71.29, 79.59, 111.98, 114.60, 121.65, 131.35, 144.23, 146.67; IR: 3436 (O—H stretch), 1591, 1515, 1272, 1098, 1030, 851 cm−1; MS (ESI) 336.2 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.I[CH2:14][C:15]([F:18])([F:17])[F:16].[H-].[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Reactant: FC(F)(F)CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1c2cc(Br)ccc2ccn1CC(F)(F)F
Temperature: 25 °C
Yield: 22 %

Procedure:
To a stirred solution of 7-bromoisoquinolin-1(2H)-one (5 g, 22.3 mmol) and iodotrifluoroethane (4.9 g, 23.4 mmol) in dimethylacetimide cooled to 5° C. was added sodium hydride 60% wt (0.89 g 22.3 mmol) portion wise over 5 minutes. After complete addition reaction mixture allowed to warm up to room temperature over 2 hours and then heated at 50° C. for 24 hours. Reaction mixture was evaporated to leave a residue, which was diluted with ethyl acetate (200 ml) and water (200 ml). The aqueous layer was further extracted with ethyl acetate (2×50 ml) and organic layers were combined and washed with saturated aqueous bicarbonate (200 ml), brine (200 ml) and dried over Magnesium sulfate powder, filtered and concentrated under reduced pressure to leave a residue and purified using column chromatography eluting with 50% ethyl acetate/petrol ether to give a yellow solid which was still impure by LCMS (1.53 g, 22% yield)
Reaction SMILES: C[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:16]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:13])([F:14])[F:15])[CH:8]=3)[N:3]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: Cc1ccc2cc(C(F)(F)F)ccc2n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2nc(N3CCNCC3)ccc2c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a solution of 2-methyl-6-(trifluoromethyl)quinoline (1.5 g, 7.10 mmol) in N,N-dimethylformamide (50 ml) was added piperazine (2.8 g, 32.51 mmol) and potassium carbonate (1.8 g, 12.93 mmol). The resulting solution was stirred for 3 hours at 140° C. and then quenched by the addition of water (200 ml). The crude product was extracted with ethyl acetate (3×100 ml) and the organic layers were combined. The resulting mixture was washed with saturated aqueous sodium chloride (3×100 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum. The crude residue was purified by silica gel chromatography using 1-5% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated to afford 2-(piperazin-1-yl)-6-(trifluoromethyl)quinoline as a brown solid (1.3 g, 65%). (ES, m/z): [M+H]+ 282; 1H NMR (300 MHz, DMSO): δ 8.17-8.23 (t, J=9.3, 2H), 7.66-7.77 (m, 2H), 7.63 (d, J=9.3 Hz, 1H), 3.78-3.81 (t, J=4.5 Hz, 4H), 2.92-2.96 (t, J=4.5 Hz, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@:14]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)([S:16][CH2:17][Si](C)(C)C)[CH2:13][C@H:12]1[C:34]([OH:36])=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@:14]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)([S:16][CH3:17])[CH2:13][C@H:12]1[C:34]([OH:36])=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of (2S,4R)-1-(benzyloxycarbonyl)-4-(biphenyl-4-yl)-4-((trimethylsilyl)methylthio)pyrrolidine-2-carboxylic acid (453 mg, 0.872 mmol) in THF (10 mL) was added Tetrabutylammonium fluoride (2.61 mL, 2.61 mmol). The formed light yellow solution was stirred at room temperature overnight. Diluted with EtOAc, washed with 5% citric acid, and brine, dried over MgSO4, filtered, evaporated, to afford the desired product (2S,4R)-1-(benzyloxycarbonyl)-4-(biphenyl-4-yl)-4-(methylthio)pyrrolidine-2-carboxylic acid (390 mg, 0.784 mmol, 90% yield) as a white foam. LC-MS (retention time: 3.14 min, method B), MS m/z 448 (M+H), 400 (M-MeSH).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1O.CI>CC(C)=O>[Br:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[O:4][CH3:1]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(Cl)cc1Br
Temperature: 25 °C

Procedure:
A mixture of K2CO3 (68 g, 0.5 mol), 2-bromo-4-chorophenol (50 g, 0.24 mol) and MeI (42.6 g, 0.3 mol) in acetone (1000 mL) was heated to reflux for 5 h and then cooled to room temperature. The solid was filtered off and washed with dichloromethane (100 mL×3). The combined filtrate was concentrated to dryness. The residue was diluted with diethyl ether (500 mL) and washed HCl (1 M, 100 mL×2), H2O (100 mL×2) and brine (200 mL). The separated organic layer was dried over Na2SO4 and concentrated to give 2-bromo-4-chloroanisole 5a as light yellow liquid. 1H NMR (CDCl3): δ 7.52 (d, J=2.8 Hz, 1H), 7.24 (q, J1=8.8 Hz, J2=2.8 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:19][C:20]1[CH:25]=[C:24]([O:26]C)C=C[C:21]=1[N:28]=C=S>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:2]=1[NH:1][NH:28][CH2:21][CH:20]([Cl:19])[CH2:25][CH2:24][OH:26]
Reactant: COc1ccc(N=C=S)c(Cl)c1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NNCC(Cl)CCO)c1NCCCCO
Yield: 45.3 %

Procedure:
A solution of methyl 3-amino-4-chloro-2-[(4-hydroxybutyl)amino]benzoate (2.00 g, 7.33 mmol) and 2-chloro-1-isothiocyanato-4-methoxybenzene (2.94 g, 14.7 mmol) in tetrahydrofuran (20 mL) was stirred for 36 h at 70° C. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel eluting with a 50% ethyl acetate/n-hexane mixture to give the title compound as a pale yellow oil (1.57 g, 3.32 mmol, 45%).
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].C1(=O)O[CH2:10][CH2:9][O:8]1.C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:3][C:2]([F:5])([F:4])[CH2:1][O:6][CH2:10][CH2:9][OH:8]
Reactant: O=C1OCCO1
Reactant: OCC(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Product: OCCOCC(F)(F)F

Procedure:
Trifluoroethanol (36 mL, 494 mmol), ethylene carbonate (66.0 g, 741 mmol), triethylamine (70 mL, 494 mmol) and tetrabutylammonium bromide (3.20 g, 9.90 mmol) were combined and the reaction mixture heated to reflux for 24 hours. The reaction mixture was distilled at atmospheric pressure, yielding the title product in the range 132° C. to 142° C.
Reaction SMILES: CN(C)/[N:3]=[CH:4]/[C:5]([CH3:7])=[CH2:6].C(OC(=O)C)(=O)C.Br[C:17]1[C:18](=[O:25])[CH:19]=[C:20]([CH3:24])[C:21](=[O:23])[CH:22]=1>CC#N>[CH3:7][C:5]1[CH:4]=[N:3][C:22]2[C:21](=[O:23])[C:20]([CH3:24])=[CH:19][C:18](=[O:25])[C:17]=2[CH:6]=1
Reactant: C=C(C)/C=N/N(C)C
Reactant: CC1=CC(=O)C(Br)=CC1=O
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC1=CC(=O)c2cc(C)cnc2C1=O
Temperature: 25 °C

Procedure:
(E)-1,1-dimethyl-2-(2-methylallylidene)hydrazine (2.18 g, 19.50 mmol, 1.3 equiv.) and acetic anhydride (19.15 mL) were added in 250 mL of MeCN and stirred at room temperature. 2-bromo-5-methylcyclohexa-2,5-diene-1,4-dione (3 g, 14.9 mmol, 1 equiv.) in 125 mL of MeCN was then added dropwise (slowly during 60 min). The reaction mixture was stirred at room temperature during 120 minutes.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]2[NH:9][C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:31][Si:32]([CH3:39])([CH3:38])[CH2:33][CH2:34][O:35][CH2:36]Cl>CN(C)C=O>[C:1]([C:5]1[CH:24]=[CH:23][C:8]2[N:9]([CH2:36][O:35][CH2:34][CH2:33][Si:32]([CH3:39])([CH3:38])[CH3:31])[C:10]([CH2:12][CH:13]3[CH2:16][CH:15]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])[CH2:14]3)=[N:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CON(C)C(=O)C1CC(Cc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC(Cc2nc3cc(C(C)(C)C)ccc3n2COCC[Si](C)(C)C)C1
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a solution of 3-[(5-tert-butyl-1H-1,3-benzodiazol-2-yl)methyl]-N-methoxy-N-methylcyclobutane-1-carboxamide (80%, 2.02 g, 4.91 mmol) in N,N-dimethylformamide (40 ml) under N2 was added potassium carbonate (1.36 g, 9.81 mmol) and the reaction was stirred for 1 h. 2-(Trimethylsilyl)ethoxymethyl chloride (1.31 ml, 7.36 mmol) was added slowly, and stirring maintained for 20 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was taken up in EtOAc (50 ml) and washed with water (3×50 ml), then brine (50 ml) before being dried (MgSO4) and concentrated. The crude material was purified by silica flash column chromatography, eluting with 50-100% EtOAc in heptane to afford the title compound (1.21 g, 54%) as a colourless gum: MS (ESI+) for C25H41N3O3Si m/z 461.0 [M+H]+; LC purity 97% (UV), 100% (ELS), (ret. time, 1.98 min); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.58-7.89 (m, 1H), 7.33 (s, 2H), 5.39-5.53 (m, 2H), 3.65 (s, 3H), 3.49-3.58 (m, 2H), 3.41 (br. s., 1H), 3.10-3.23 (m, 3H), 3.03 (s, 3H), 2.32-2.63 (m, 2H), 2.00-2.18 (m, 2H), 1.32-1.45 (m, 9H), 0.91 (td, J=8.1, 4.9 Hz, 2H), −0.13-0.07 (m, 9H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[N:12]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[N:24][N:23]=[N:22]4)=[N:19][CH:20]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[CH:26]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:26]1([S:32]([N:2]2[CH2:3][CH2:4][CH:5]([N:8]3[N:12]=[C:11]([CH2:13][O:14][C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH:25]=[N:24][N:23]=[N:22]5)=[N:19][CH:20]=4)[CH:10]=[N:9]3)[CH2:6][CH2:7]2)(=[O:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=S(=O)(Cl)C1CCCCC1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cnn(C2CCNCC2)n1
Agent: Cl
Product: O=S(=O)(C1CCCCC1)N1CCC(n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CC1

Procedure:
The title compound was synthesized using Intermediate 15 and cyclohexanesulfonyl chloride in a similar manner as described in Example 39. 1H NMR (DMSO-d6): δ 10.08 (1H, s), 8.42 (1H, d), 8.01 (1H, d), 7.95 (1H, s), 7.86 (1H, dd), 3.52 (2H, s), 4.74 (1H, m), 3.68 (2H, m), 3.11 (3H, m) 2.51 (1H, m), 2.17 (2H, m) 1.92 (3H, m), 1.73 (1H, m), 1.23 (7H, m).
Reaction SMILES: [H-].[Na+].[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([NH2:17])[CH:11]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:21]1[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=1.Cl>O.C1COCC1>[C:3]([SiH2:7][O:8][C:9]([CH3:19])([CH3:18])[C:10]1[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([NH:17][C:21]2[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=2)[CH:11]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cnc(N)cc1C(C)(C)O[SiH2]C(C)(C)C
Reactant: N#Cc1cnc(Cl)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(Nc2ncc(C#N)s2)cc1C(C)(C)O[SiH2]C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An oven dried flask under N2 was charged with NaH (60% dispersion, 185 mg, 4.63 mmol). 5 mL of anhydrous THF was added followed by addition of 4-(tert-butyl-dimethyl-silanyloxymethyl)-5-methyl-pyridin-2-ylamine (9-6, 0.487 g, 1.93 mmol) and 2-chloro-5-cyanothiazole (1-2, 0.391 g, 2.70 mmol). The resulting solution was heated to reflux. After 1 hour the reaction was allowed to cool to room temperature and was then diluted with water. The pH was adjusted to 7 with 1 M HCl. The resulting precipitate was filtered and washed with water to afford 9-7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][N+:19]([O-])=O)[CH2:9][P:10]([CH3:17])(=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:19][CH2:18][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][P:10]([CH3:17])(=[O:16])[O:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)COP(C)(=O)CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)COP(C)(=O)CC(CN)c1ccc(Cl)cc1

Procedure:
A solution of 6.8 g of isobutyl 2-(4-chlorophenyl)-3-nitro-propyl(methyl)phosphinate in 80 ml of ethanol is added to 64 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel slurry and the resulting mixture is hydrogenated at 1 bar until hydrogen uptake ceases. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give isobutyl 3-amino-2-(4-chlorophenyl)-propyl(methyl)phosphinate as a viscous oil, 31P N.M.R. spectrum: δ=+54.0 and +53.4 ppm (CDCl3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])C.[CH3:24][O-:25].[Na+]>>[CH3:1][O:3][C:4](=[O:23])[C:5]1[C:10]([O:25][CH3:24])=[CH:9][C:8]([C:12]2[C:13]([CH2:20][CH3:21])=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:18][CH3:19])=[N:7][C:6]=1[CH3:22]
Reactant: C[O-]
Reactant: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
Agent: [Na+]
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)c(C)n1
Temperature: 65 °C

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester (165 mg, 0.5 mmol) and sodium methoxide (0.5 M in methanol, 4 mL, 2.0 mmol) is heated at 65° C. for 16 hours. The volatile material is removed in vacuo and the residue is partitioned between ethyl acetate (50 ml) and water (20 mL). The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×20 mL). The combined organic extract is dried and concentrated in vacuo. The crude product is purified by PTLC (hexanes/ethyl acetate 4:1) to give 6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-nicotinic acid methyl ester. 1H NMR: (CDCl3) 7.26 (m, 2H), 7.13 (d, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 2.56 (s, 3H), 2.32 (m, 4H), 1.04 (t, 6H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[C:15]3[C:10]([C:11](=[O:27])[C:12]([C:22]([O:24]CC)=[O:23])=[CH:13][N:14]3[CH:18]([CH3:21])[CH2:19]Cl)=[CH:9][C:8]=2[F:28])[CH2:3]1.C(O)C.[OH-].[K+]>O>[NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[C:15]3[C:10]([C:11](=[O:27])[C:12]([C:22]([OH:24])=[O:23])=[CH:13][N:14]3[C:18]([CH3:21])=[CH2:19])=[CH:9][C:8]=2[F:28])[CH2:3]1
Reactant: CCOC(=O)c1cn(C(C)CCl)c2c(F)c(N3CCC(N)C3)c(F)cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(N)C3)c(F)c21
Yield: 39.2 %

Procedure:
159 mg (0.38 mmol) of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(1-chloroprop-2-yl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (Compound No.1) prepared in Example 1 was dissolved into 20 ml of ethanol. To this was added 65 mg (1.15 mmol) of pulverized potassium hydroxide and the mixture was heated under refluxing for 14 hours. 3 ml of water was added and the mixture was heated under refluxing for a further 3 hours. After cooling, the reaction mixture was concentrated under reduced pressure, the residue was washed with water, and dried to obtain a crude product. The crude product was purified by silica gel column chromatography (chloroform:methanol=5:1) to obtain 52 mg of light yellow crystals of 7-(3-amino-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-4-oxo-1-(prop-1-en-2-yl)-quinoline-3-carboxylic acid (Compound No. 19).
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[O:9])=[C:6]([I:16])[C:5]([C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[O:18])=[C:4]([I:25])[C:3]=1[NH:26][C:27]([NH:29][C:30]1[C:35]([I:36])=[C:34]([C:37]([NH:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43])=[O:38])[C:33]([I:45])=[C:32]([C:46]([NH:48][CH2:49][CH:50]([OH:53])[CH2:51][OH:52])=[O:47])[C:31]=1[I:54])=[O:28].[OH-].[Na+].Br[CH2:58][CH2:59][OH:60]>O>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[O:9])=[C:6]([I:16])[C:5]([C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[O:18])=[C:4]([I:25])[C:3]=1[N:26]([CH2:58][CH2:59][OH:60])[C:27]([NH:29][C:30]1[C:35]([I:36])=[C:34]([C:37]([NH:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43])=[O:38])[C:33]([I:45])=[C:32]([C:46]([NH:48][CH2:49][CH:50]([OH:53])[CH2:51][OH:52])=[O:47])[C:31]=1[I:54])=[O:28]
Reactant: O=C(Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCC(O)CO)c1c(I)c(NC(=O)N(CCO)c2c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c2I)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 60 h

Procedure:
N,N'-bis[2,4,6-triiodo-3,5-bis(2,3-dihydroxypropylaminocarbonyl)phenyl]-urea (2.0 g, 1.4 mmol) was dissolved in water (13 ml) containing 2M NaOH (7 ml). 2-Bromoethanol (1 g, 8.4 mmol) was added and the mixture was stirred at ambient temperature for 60 h, treated with a strongly acidic ion exchange resin (Amberlyst 15) evaporated and purified by preparative HPLC. Yield: 1.45 g (70%) of the product as a white solid. 1H NMR (DMSO-d6): 9.10-9.38 (m, 1H, NH), 7.90-8.65 (m, 4H, NH), 3.02-3.91 (m, 24H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.Cl.[CH:12](=O)/[CH:13]=[CH:14]/[CH3:15].[NH4+].[OH-]>>[F:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([O:9][CH3:10])[CH:3]=1)[N:6]=[C:14]([CH3:15])[CH:13]=[CH:12]2
Reactant: C/C=C/C=O
Reactant: COc1cc(F)ccc1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(F)cc2ccc(C)nc12
Yield: 99.8 %

Procedure:
To 4-fluoro-2-methoxyaniline (370 mg, 2.62 mmol) in refluxing 6N HCl (5 mL) was added dropwise (E)-but-2-enal (367 mg, 5.24 mmol). The reaction was heated to reflux for 2 hours then cooled and neutralized with NH4OH. The aqueous phase was extracted with DCM, and the combined organic phases dried over MgSO4 and concentrated to yield 6-fluoro-8-methoxy-2-methylquinoline (500 mg, 99.8% yield) as a brown solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][CH:12]=[CH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH3:10]>ClC(Cl)(Cl)Cl>[Br:1][C:13](=[CH:12][O:11][CH2:9][CH3:10])[C:14](=[O:19])[C:15]([F:17])([F:18])[F:16]
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC=C(Br)C(=O)C(F)(F)F
Yield: 78.5 %

Procedure:
9.8 g (0.055 mole) of N-bromosuccinimide and 100 mg azoisobutyronitrile are added to a solution of 8.4 g (0.05 mole) of 4-ethoxy-1,1,1-trifluoro-but-3-en-2-one in 50 ml of tetrachloromethane. The mixture is then refluxed for 8 hours, the cooled solution is filtered and the filtrate is concentrated. 13.4 g of a crude product are obtained whiose distillation under reduced pressure gives 9.7 g of 3-bromo-4-ethoxy-1,1,1-trifluorobut-3-en-2-one.