Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Yield: 69.5 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (50 mg, 0.16 mmol), 5-aminovaleric acid (945 mg, 8.06 mmol) and NaOMe solution (12 mL, 6.05 mmol, 0.5 M in MeOH) was refluxed for 48 h. Solvent was evaporated in vacuo, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-60% EtOAc/hexanes+2% AcOH) to give 44 mg of the title compound as a light yellow solid. MS: (+) m/z 396.08 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=2)C=CC=CC=1.N12CCCCC1C=NCCC2.Cl>O1CCOCC1.O>[CH3:35][O:34][C:32]1[CH:31]=[C:30]([O:36][CH3:37])[N:29]=[C:28]([NH:27][C:26]([NH:18][S:15]([CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]2[O:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)(=[O:17])=[O:16])=[O:25])[N:33]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CSc1nnc(-c2ccccc2CS(N)(=O)=O)o1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Cc2ccccc2-c2nnc(SC)o2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
To a solution containing 0.62 g of the sulfonamide prepared in Example 3 contained in 10 ml of p-dioxane was added 0.6 g of phenyl(4,6-dimethoxy pyrimidin-2-yl)carbamate followed by dropwise addition of 0.33 g of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU). The solution was stirred at room temperature for two hours then diluted with about 100 ml of water. The clear solution was acidified with concentrated hydrochloric acid (red to litmus paper), to give a viscous oil. The oil was triturated by decanting off the aqueous solvent and stirring the oil residue in about 5 ml of acetonitrile. After filtering the suspension, the solid residue was washed with 1×5 ml of warm ethyl acetate to give 0.26 g of the subject compound; m.p. 174°-177° C.
Reaction SMILES: [C:1]([C:4]1[CH:40]=[CH:39][C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]([N:16]([C:18]2[C:19]([Cl:38])=[C:20]([C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:21][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[N:31]=[C:30]([CH3:33])[CH:29]=[CH:28]3)[CH3:17])=[O:15])=[O:11])=[CH:6][CH:5]=1)([OH:3])=O.Cl.[CH2:42]([NH2:44])[CH3:43].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Cl:38][C:19]1[C:18]([N:16]([C:14](=[O:15])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH:44][CH2:42][CH3:43])=[CH:40][CH:39]=2)[CH3:17])=[CH:36][CH:35]=[C:34]([Cl:37])[C:20]=1[CH2:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[C:30]([CH3:33])[CH:29]=[CH:28]2
Reactant: CCN
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)O)cc4)c3Cl)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
To a mixture of 8-[3-[N-(4-carboxycinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), ethylamine hydrochloride (16.9 mg) and N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (32.2 mg) and 1-hydroxybenzotriazole (30.4 mg), and the mixture was stirred for 6 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride--methanol) to give 8-[2,6-dichloro-3-[N-[4-(ethylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methylquinoline (91 mg).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([NH:21][C@@H:22]1[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]1[OH:24])[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].[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>O.C1COCC1>[C@@H:22]1([N:21]([CH2:7][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])[C:33](=[O:36])[CH:34]=[CH2:35])[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]1[OH:24]
Reactant: CCCCCCCCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)N(CCCCCCCCCCCCCC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
A solution of 85 mmol (9 g) of sodium carbonate in 25 ml of water is added to a solution of 13.7 mmol (4 g) of N-tetradecyl-β-D-glucopyranosylamine in 190 ml of THF. A solution of 26 mmol (2.0 ml) of acryloyl chloride in 20 ml of THF is added dropwise over one hour. The THF is evaporated off and the acylamidosugar is then extracted with 300 ml of ethyl acetate. The organic phase is washed with a saturated solution of NaHCO3, dried over MgSO4 and evaporated at reduced pressure.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:22]=[C:23]([C:29]2[S:33][C:32]([C:34]([O:36]CC)=[O:35])=[N:31][C:30]=2[CH3:39])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][O:27][C:26]1[C:21]([C:8]2[CH:9]=[CH:10][C:5]([S:2](=[O:4])(=[O:3])[NH2:1])=[CH:6][CH:7]=2)=[CH:22][C:23]([C:29]2[S:33][C:32]([C:34]([OH:36])=[O:35])=[N:31][C:30]=2[CH3:39])=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1nc(C)c(-c2ccc(OC)c(Br)c2)s1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2sc(C(=O)O)nc2C)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 92.5 °C
Yield: 88.1 %

Procedure:
4-aminosulfonylbenzene boronic acid (1.15 g, 5.73 mmol) and potassium carbonate (1.97 g, 14.31 mmol) were added to a solution of ethyl 5-(3-bromo-4-methoxyphenyl)-4-methylthiazole-2-carboxylate (Step 1, 1.70 g, 4.77 mmol) in a mixture of toluene:ethanol (15 ml:40 ml) in a tube at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes and to it was added tetrakis(triphenylphosphine)palladium (0) (0.28 g, 0.24 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was then washed with 10% methanol in dichloromethane (3×30 ml). The filtrate was dried over sodium sulphate and was concentrated under reduced pressure to obtain the title compound 8b (1.70 g, 88.08%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]=O)[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[CH2:39][NH2:40].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[CH2:39][NH:40][CH2:26][C:9]1[CH:8]=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:28])[C:16]2[O:15][CH2:14][C@H:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]3[C:23](=[O:25])[NH:24][C:10]=1[C:11]=23
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1noc(C)c1-c1cc(C=O)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CNCc2cc(-c3c(C)noc3C)c3c4c2[nH]c(=O)n4[C@@H](c2ccccn2)CO3)c(OC)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 114.2 %

Procedure:
A solution (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbaldehyde (250 mg, 0.664 mmol) in ethanol (12.5 mL) was treated with 1-(2,4-dimethoxyphenyl)methanamine [Aldrich #: 432725](150 μL, 0.996 mmol) and acetic acid (20.0 μL, 0.352 mmol) and heated at 60° C. for 1 h. The reaction mixture was cooled to room temperature, treated with sodium cyanoborohydride (210 mg, 3.3 mmol) and stirred at room temperature for 3 h. The reaction mixture was then quenched with acetic acid (1 mL) and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the desired product (0.40 g, 97%) as a single enantiomer which was used without further purification. LCMS calculated for C29H30N5O5 (M+H)+: m/z=528.2. found: 528.0.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1CCCCC1.[Cu]I.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>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: C[Si](C)(C)C#Cc1ccc(N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 1-(methylsulfonyl)-4-(4-bromophenyl)piperazine (4.79 g, 15 mmol, prepared as in example 3), trimethylsilylacetylene (4.15 mL, 30 mmol), Copper (I) iodide (31 mg, 0.17 mmol) and triphenylphosphine (80 mg, 0.3 mmol) in piperidine (60 mL) at 20° C. was added dichlorobis(triphenylphosphine)palladium(II) (31 mg, 45 μmol). The reaction was warmed to 105° C. and stirred for 8 hours under an inert atmosphere. After cooling, the suspension was filtered and washed with toluene. The solid was dissolved in CH2Cl2, washed with water and filtered through silica, washing with CH2Cl2. The filtrate was concentrated and the resulting suspension filtered, washing well with CH2Cl2/iHexane to give 1-(methylsulfonyl)-4-[4-(trimethylsilylethynyl)phenyl]piperazine as a white powder (3.05 g, 9.06 mmol, 60
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[S:21][C:22]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:32]1[C:41]([CH3:42])=[CH:40][C:39]2[C:38]([CH3:44])([CH3:43])[CH2:37][CH2:36][C:35]([CH3:46])([CH3:45])[C:34]=2[CH:33]=1>>[CH3:42][C:41]1[C:32](/[C:26](/[Si:27]([CH3:28])([CH3:29])[CH3:30])=[CH:25]/[C:22]2[S:21][C:20]([CH2:19][OH:18])=[CH:24][CH:23]=2)=[CH:33][C:34]2[C:35]([CH3:46])([CH3:45])[CH2:36][CH2:37][C:38]([CH3:44])([CH3:43])[C:39]=2[CH:40]=1
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)s1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Product: Cc1cc2c(cc1/C(=C/c1ccc(CO)s1)[Si](C)(C)C)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure A, 5-[(trimethylsilyl)ethynyl]thiophen-2-ylmethyl tert-butyldiphenylsilyl Ether (Compound 13, 0.75 g, 1.8 mmol) and 2-bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (0.45 g, 1.67 mmol) were coupled to give the title compound.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([O:14][C@H:15]1[C@H:20](O)[C@@H:19]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:18][CH2:17][CH2:16]1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>N1C=CC=CC=1>[C:6]([O:14][C@@H:15]1[CH2:16][CH2:17][O:18][C@H:19]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:20]1[Cl:4])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O[C@@H]1CCO[C@H](COCc2ccccc2)[C@H]1O)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O[C@@H]1CCO[C@H](COCc2ccccc2)[C@@H]1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sulfonyl chloride (29 μl) was added to a solution of 1,5-anhydro-3-O-benzoyl-6-O-benzyl-2-deoxy-D-arabino-hexitol obtained by the method described in J. Org. Chem. 67. 3346-3354 (2002) (94 mg) in pyridine (27 mg) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. Water was added, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (27 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Br)=[CH:4][CH:3]=1.O1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:4]2[CH:5]=[CH:6][CH:11]=[C:2]([N:1]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:3]=2)=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: Nc1ccc(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Nc1ccc(-c2cccc(N3CCOCC3)c2)c2ccccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
The above intermediate (1.49 g, 3.51 mmol) and 1-amino-4-bromonaphthalene (0.69 g, 3.11 mmol) were dissolved in 20 mL anhydrous 1,4-dioxane in a sealable tube under inert gas atmosphere. The solution was degased and purged with nitrogen (2×). Tetrakis(triphenylphosphine)palladium(0) (0.21 g, 0.18 mmol) was added and the solution was degassed and purged with nitrogen again (2×). The tube was sealed and heated to 100° C. for 17 h. After cooling to room temperature the mixture was diluted with EtOAc, saturated aqueous potassium carbonate solution (10 mL) was added and the mixture was stirred for 1 h at room temperature. The mixture was filtered over diatomaceous earth and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated to dryness. Purification of the residue by flash chromatography afforded 0.363 g (1.19 mmol, 38%) of title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21])=[O:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:21])([F:22])[F:23])[C:2]([O:4][CH2:5][CH3:6])=[O:3])=[O:11]
Reactant: O=C(NNc1ccccc1C(F)(F)F)c1ccccc1Cl
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N(NC(=O)c1ccccc1Cl)c1ccccc1C(F)(F)F

Procedure:
1.8 ml (19 mmol) of ethyl chloroformate are added dropwise while cooling to a mixture of 4.28 g (14 mmol) of 2-chloro-N'-(α,α,α-trifluoro-o-tolyl)-benzhydrazide and 2.7 ml (19 mmol) of triethylamine in 30 ml of toluene. The reaction mixture is heated at the reflux temperature for a further 4 hours and then extracted with diethyl ether against water and sodium bicarbonate solution. The organic phase is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residual oil is then purified by chromatography using ethyl acetate/n-hexane (1:4) as the eluent. In this manner there is obtained ethyl 3-(2-chlorobenzoyl)-2-(α,α,α-trifluoro-o-tolyl)-carbazate as an almost colourless oil, IR spectrum (CHCl3): 3405, 1735, 1710 cm-1 ; 1H-NMR (CDCl3): 4.28 (q,OCH2CH3).
Reaction SMILES: O=O.[CH3:3][C:4](=[CH:6][CH2:7][CH2:8]/[C:9](=[CH:11]/[CH2:12][OH:13])/[CH3:10])[CH3:5].C(OCC)(=O)C>O>[CH3:3][C:4](=[CH:6][CH2:7][CH2:8][C@H:9]([CH2:11][CH2:12][OH:13])[CH3:10])[CH3:5]
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: O=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)=CCC[C@@H](C)CCO
Temperature: 20 °C
Reaction time: 68 h
Yield: 86.4 %

Procedure:
A 185 ml autoclave was charged in a glove box (O2 content<1 ppm) with 8.8 g geraniol VIII [(E)-3,7-dimethyl-2,6-octadien-1-ol], 75.2 mg ((S)-MeO-BIPHEP-TS-Na)Ru(OCOCF3)2, 31 ml ethyl acetate and 8 ml water. The hydrogenation was effected under vigorous stirring at 20 ° C. and 60 bar. After 68 hours the conversion amounted to 96%. The organic phase was separated and evaporated at 45 ° C./17 mbar. The residue consisted 92% (R)-Citronellol (A) and 4% by-product B. For purification the clear residue was destilled at 60° C./0.2 mbar. There were obtained 7.7 g (R)-Citronellol (A) [(R)-3,7-dimethyl-6-octen-1-ol] as a colourless oil; e.e. 97%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][S:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[C:8]=1[Cl:23])[CH3:2].OO.C(O)=[O:28].C(Cl)Cl>O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][S:6]([C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[C:8]=1[Cl:23])=[O:28])[CH3:2]
Reactant: O=CO
Reactant: CCOC(=O)CSc1ccc2c(-c3ccccc3F)noc2c1Cl
Agent: OO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CS(=O)c1ccc2c(-c3ccccc3F)noc2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.0g (8.2 mmole) of ethyl[[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]thio]acetate, 2.5g of a 30% H2O2 solution, 10 ml of formic acid and 50 ml of CH2Cl2 was stirred at room temperature for two hours. The reaction was diluted with water and extracted three times with CH2Cl2. The organics were combined, washed with dilute NaHCO3 and dried over MgSO4. The solution was concentrated at reduced pressure to a yellow oil which solidified to a cream-colored solid, 3.0g (94%) of ethyl[[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]sulfinyl]acetate, m.p. 115°-118° C. The solid was recrystallized from ether to afford pale yellow prisms of ethyl[[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]sulfinyl]acetate, m.p. 120°-121° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[N:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1B(O)O.C1(C)C=CC=CC=1>CCO>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:8]1[N:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: OB(O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cccnc1-c1ccc(F)cc1F
Temperature: 82 °C
Reaction time: 8 h

Procedure:
To a nitrogen purged 3.0 L, 4-necked flask, fitted with an overhead stirrer, thermocouple, heating mantle, nitrogen outlet and reflux condenser, was charged Pd(Ph3)4 (5.0 g, 4.33 mmoles, 0.005 eq), sodium carbonate (92.6 g, 874 mmoles, 1.3 eq), ethyl 2-chloronicotinate, 1 (126.0 g, 678 moles, 1.0 eq), 2,4-difluorophenylboronic acid, 2 (125 g, 791 mmoles, 1.2 eq), followed by 0.5 L of toluene and 125 mL denatured EtOH. The reaction was heated to 82° C. with vigorous stirring under N2 overnight (completeness of reaction determined by HPLC and TLC). The reaction was cooled to room temperature, the mixture filtered through a small pad of Celite® and the solvents removed under vacuum at 55° C. The residue was dissolved in EtOAc, washed, dried (MgSO4), filtered through Celite® again, and concentrated. The product was obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>>[C:23]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][CH:22]=4)[N:19]=[CH:18][CH:17]=[CH:16]5)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc2ncccc2c1)c1cnc2ccc(-c3ccccc3)nn12

Procedure:
A 48 mL sealed tube was charged with (6-chloroimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.530 g, 1.72 mmol), phenylboronic acid (0.314 g, 2.58 mmol), cesium carbonate (1.68 g, 5.15 mmol), PdCl2(dppt)-CH2Cl2 adduct (0.0701 g, 0.0858 mmol), 1,4-dioxane (6.31 ml, 73.8 mmol), and water (1.11 ml, 61.8 mmol), flushed with argon, sealed, then placed in an 80° C. oil bath for 8 hours. The mixture was concentrated then triturated with water, followed by MeOH/DCM to give (6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone as a reddish brown solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Na+].Cl>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:27])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([O:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[C:8]2[CH3:26]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Oc3ccc(Cl)cc3)c(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1Oc1ccc(Cl)cc1

Procedure:
A solution of [8-chloro-3-(4-chlorophenoxy)-2,4-dimethylquinolin-5-yloxy]acetic acid methyl ester (0.20 g), methanol (5.0 mL), water (1.0 mL) and 5.0 M aqueous sodium hydroxide solution (1.0 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 1 by the addition of 1.0 M hydrochloric acid and the methanol removed under reduced pressure. The residue was purified by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water (40% to 98% of organic modifier) to afford title compound as a yellow-green solid, 0.025 g.