Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:20]([CH3:21])[CH:19]=[CH:18][C:5]2=[N:6][C:7]=1[C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9].[CH3:22][C:23]1[C:27](B2OC(C)(C)C(C)(C)O2)=[C:26]([CH3:37])[NH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:22][C:23]1[C:27]([C:2]2[CH:3]=[C:4]3[N:20]([CH3:21])[CH:19]=[CH:18][C:5]3=[N:6][C:7]=2[C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[C:26]([CH3:37])[NH:25][N:24]=1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1n[nH]c(C)c1-c1cc2c(ccn2C)nc1[C@H](C)NC(=O)OC(C)(C)C

Procedure:
A solution of (S)-tert-butyl (1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (2 g, 5.65 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1160 mg, 5.20 mmol) and PdCl2(dppf)-CH2Cl2 adduct (147 mg, 0.180 mmol) in dioxane (3500 μL) and aqueous 3M potassium carbonate solution (5400 μL, 16 mmol) was heated at 120° C. for 5 hours in a microwave reactor. The mixture was diluted with ethyl acetate (177 mL), washed with saturated ammonium chloride (177 mL) and brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified on silica gel, eluting with EtOAc to give the title compound. ESI-MS m/z [M+H]+ calc'd for C20H27N5O2, 370.2. found 370.6.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1>>[NH2:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: Nc1cc(F)cc(B(O)O)c1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3cc(N)cc(F)c3)ccn2c1=O
Yield: 86.7 %

Procedure:
Methyl 8-(3-amino-5-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 3-amino-5-fluoro-phenyl-boronic acid (80 mg, 0.51 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (108 mg, 81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([S:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(O)cc2)C1
Yield: 81 %

Procedure:
(RS)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.8 g, 2.34 mmol), 4-mercaptophenol (0.49 g, 3.88 mmol, 90%) and Na2CO3 (0.37 g, 3.51 mmol) were suspended in acetonitrile (10 ml). After 20 hours refluxing, reaction mixture was concentrated. The residue was taken up in H2O (15 ml) and extracted with CH2Cl2 (3 times). The combined organic phases were dried over Na2SO4, filtered and the solvent was evaporated. The residue was chromatographed over silica gel (hexane-ethylacetate 4:1 then 2:1) to provide (RS)-3-(4-hydroxy-phenylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.56 g, 81%) as a slightly yellow solid, MS: m/e=296.4 (M+H+).(RS)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester is a known compound and has been prepared as described in WO 9734895.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:15]=1[C:16](OC)=[O:17].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:24][C:22]1[CH:21]=[CH:20][C:15]2[C:16](=[O:17])[NH:1][C:2]3[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][C:3]=3[NH:13][C:14]=2[CH:23]=1
Reactant: COC(=O)Cc1ccc(Nc2cc(Cl)ccc2C(=O)OC)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A mixture of Example 695C (0.3 g, 0.91 mmol) and TsOH.H2O (0.35 g, 1.82 mmol) in toluene (50 mL) was heated to reflux for 20 hours using a Dean-Stark trap to remove water. The reaction was cooled to room temperature, concentrated under vacuum, diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 0.21 g (81%) of the desired product. MS (DCI) m/e 317 (M+H)+, 334 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.03 (s, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.91-6.93 (m, 2H), 6.86-6.87 (m, 2H), 3.60 (s, 3H), 3.54 (s, 2H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O

Procedure:
a polysaccharide consisting of galactose, glucose and rhamnose (5:1:1) is obtained by the strain Lactobacillus bulgaricus rr (ref. 10);
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[N:3]=1>C(O)(=O)C.C(Cl)(Cl)Cl.[Zn]>[O:1]=[C:2]1[NH:3][C:4]([C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:6]([C:8]([O:10][CH3:11])=[O:9])[NH:7]1
Reactant: COC(=O)c1cc(C(=O)OC)nc(O)n1
Agent: [Zn]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)C1=CC(C(=O)OC)NC(=O)N1
Reaction time: 0.5 h

Procedure:
Dimethyl 2-hydroxypyrimidine-4,6-dicarboxylate (1.0 g. 4.7 mmol) was dissolved in warm acetic acid (17M. 70 ml) and heated to 70°. Zinc dust (1.5 g. 22.9 mmol) was added to this stirred solution portionwise over a period of 1 h. Each addition of a zinc portion was accompanied by a purple colour change of the reaction mixture. This colour slowly dissipated, then further zinc was added in similar fashion until completion. The resulting mixture was stirred at 70° for 30 min. The reaction mixture was filtered and washed with acetic acid (17M, 2×10 ml). The filtrate was evaporated to dryness under reduced pressure to give a colourless oil. The residual oil was dissolved in chloroform (100 ml), filtered and the solvent removed to give colourless crystals. The crude product was recrystallized from methanol to give dimethyl 2-oxo-1,2,3,6-tetrahydropyrimidine-4,6-dicarboxylate as colourless prisms, (283 mg. 28%) m.p. 177°-179°
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6](=[O:36])[C:7]2[CH:12]=[C:11]([C:13]3[CH:21]=[C:20]4[C:16]([C:17]([S:30]([CH3:33])(=[O:32])=[O:31])=[N:18][N:19]4COCC[Si](C)(C)C)=[CH:15][CH:14]=3)[C:10]([CH3:34])=[C:9]([F:35])[CH:8]=2)[CH2:4][CH2:3]1>>[CH:2]1([NH:5][C:6](=[O:36])[C:7]2[CH:12]=[C:11]([C:13]3[CH:21]=[C:20]4[C:16]([C:17]([S:30]([CH3:33])(=[O:32])=[O:31])=[N:18][NH:19]4)=[CH:15][CH:14]=3)[C:10]([CH3:34])=[C:9]([F:35])[CH:8]=2)[CH2:3][CH2:4]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(S(C)(=O)=O)nn(COCC[Si](C)(C)C)c2c1
Agent: Cl
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(S(C)(=O)=O)n[nH]c2c1
Yield: 75.7 %

Procedure:
Conc. hydrochloric acid ((0.5 ml) was added to a solution of N-cyclopropyl-3-fluoro-4-methyl-5-[3-(methylsulfonyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indazol-6-yl]benzamide (Intermediate 77) (0.15 g) then stirred at reflux for 12 h. The solvent was evaporated and the residue was purified by column chromatography on silica, eluting with cyclohexane:ethyl acetate (1:1 to 1:2) to give the title compound (0.085 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17](Cl)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[C:3]([C:17]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Nc1cccc(O)c1)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Temperature: 45 °C

Procedure:
A mixture of 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carbonyl chloride (15 mg, 0.05 mmol), 3-aminophenol (12.7 mg, 0.10 mmol) and potassium carbonate (7 mg, 0.05 mmol) in dichloromethane (8 mL) was heated to 45° C. overnight. The volatiles were removed in vacuo and the compound was purified by silica gel chromatography eluting with 3% methanol in dichloromethane to afford the title compound: (7.7 mg, 0.02 mmol). MS (ESI) m/z (M+H+): 383.1.
Reaction SMILES: O.C[N:3]([CH3:6])C=O.[Br:7][C:8]1[C:13]([CH3:14])=[C:12](I)[C:11]([NH2:16])=[C:10]([O:17][CH3:18])[C:9]=1[F:19]>[Cl-].[Na+].O.[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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]>[NH2:16][C:11]1[C:10]([O:17][CH3:18])=[C:9]([F:19])[C:8]([Br:7])=[C:13]([CH3:14])[C:12]=1[C:6]#[N:3]
Reactant: COc1c(N)c(I)c(C)c(Br)c1F
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: COc1c(N)c(C#N)c(C)c(Br)c1F
Temperature: 125 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Under nitrogen atmosphere, water (0.1 ml), zinc cyanide (59 mg, 0.5 mmol), 1,1′-bis(diphenylphosphino)ferrocene (67 mg, 0.12 mmol), bis(dibenzylideneacetone)palladium(0) (58 mg, 0.1 mmol) were added to an N,N-dimethylformamide (10 ml) solution of 4-bromo-3-fluoro-6-iodo-2-methoxy-5-methylphenylamine (I-44) (359 mg, 1.0 mmol), followed by stirring at 120 to 130° C. for 3 hours. After cooling to room temperature, saturated brine was added to the reaction liquid, followed by extraction twice with ethyl acetate, the organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (10:1) was concentrated under reduced pressure to obtain the entitled compound (208 mg, 80%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1([N:53]([CH3:55])[CH3:54])[CH2:10][CH2:9][C:8]([C:32]2[NH:33][C:34]3[C:39]([C:40]=2[CH2:41][CH2:42][N:43]2[CH2:52][CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44]2)=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][N:22]2[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Cl:56][Si](C)(C)C>CC(CC)=O>[ClH:56].[CH2:1]([C:5]1([N:53]([CH3:54])[CH3:55])[CH2:6][CH2:7][C:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][N:22]2[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]2)=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:32]2[NH:33][C:34]3[C:39]([C:40]=2[CH2:41][CH2:42][N:43]2[CH2:52][CH2:51][C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:44]2)=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)Cl
Agent: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2CCN2CCc3ccccc3C2)(c2[nH]c3ccccc3c2CCN2CCc3ccccc3C2)CC1
Solvent: CCC(C)=O
Product: Cl
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
1-butyl-4,4-bis-(3-(2-(3,4-dihydro-1H-isoquinolin-2-yl)ethyl)-1H-indol-2-yl)-N,N-dimethylcyclohexylamine (57 mg, 0.079 mmol) was dissolved in ethyl methyl ketone (2 ml). The solution was mixed with chlorotrimethyl silane (50 μl, 0.391 mmol) at RT. The clear reaction mixture immediately became cloudy. The mixture was stirred for 30 min at 23° C. The white precipitate was aspirated. The solid was washed with ethyl methyl ketone (3×0.5 ml) and then dried. The hydrochloride (48 mg, approx. 80%) was obtained as light beige-coloured solid.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([C:15]2OC(=O)[S:17][N:16]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]([F:33])([F:32])[F:31])=[CH2:29])[CH:25]=[C:24]([Cl:34])[CH:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]2([C:30]([F:31])([F:32])[F:33])[S:17][N:16]=[C:15]([C:13]3[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])=[C:2]([CH3:1])[CH:14]=3)[CH2:29]2)[CH:25]=[C:24]([Cl:34])[CH:23]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1cc(-c2nsc(=O)o2)ccc1C(=O)OC(C)(C)C
Product: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C

Procedure:
A solution of tert-butyl 2-methyl-4-(2-oxo-1,3,4-oxathiazol-5-yl)benzoate (50 mg) in 1,3-dichloro-5-[1-(trifluoromethyl)vinyl]benzene (5 mL, prepared according to WO 2005085216) was heated 190° C. during 10 minutes in a microwave. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate) then on preparative HPLC to give tert-butyl 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-2-methyl-benzoate (18.5 mg) as a solid. 1H-NMR (CDCl3, 400 MHz): δ=7.86 (d, 1 H), 7.54-7.64 (m, 2 H), 7.41 (t, 1 H), 7.31 (s, 2 H), 4.23 (d, 1 H), 3.88 (d, 1 H), 2.61 (s, 3 H), 1.61 ppm (s, 9 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4]/[CH:5]=[CH:6]\[Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].BrC/C=C\[Sn](CCCC)(CCCC)CCCC.N1CCCC1>>[CH2:8]([Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])/[CH:6]=[CH:5]\[CH2:4][N:3]1[CH2:1][CH2:2][CH2:21][CH2:20]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Agent: CCCC[Sn](/C=C\CBr)(CCCC)CCCC
Solvent: C1CCNC1
Product: CCCC[Sn](/C=C\CN1CCCC1)(CCCC)CCCC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 11 starting from ((Z)-3-bromoprop-1-enyl)tributylstannane (Intermediate 12) and pyrrolidine.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[CH:11][C:7]=1[C:8](O)=[O:9]>CN(C)C=O>[F:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F

Procedure:
Thionyl chloride (2.9 L), 2.5 kg 2,3,4,5-tetrafluorobenzoic acid and 14.5 ml dimethylformamide were charged to a 12 L reaction vessel and warmed at 90°-95° C. for about 90 minutes. The excess thionyl chloride was first removed at atmospheric pressure, then in vacuo. The residue was distilled on a steam bath at water pump pressure collecting the fraction with b.p. 65°-70° C. at about 15 mm resulting in 2635 g (96.2%) of pale yellow distillate.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:40])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:36][CH2:37][CH2:38]Br)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:41]([O:48]CC)([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44]>>[CH2:43]([O:42][P:41]([CH2:38][CH2:37][CH2:36][O:35][C:12]1[CH:11]=[C:10]([C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:40])[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=1)(=[O:48])[O:45][CH2:46][CH3:47])[CH3:44]
Reactant: CCOP(OCC)OCC
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCBr)cc(C(=O)OCc2ccccc2)c1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCP(=O)(OCC)OCC)cc(C(=O)OCc2ccccc2)c1
Yield: 59.6 %

Procedure:
A mixture of 4.91 g (7.95 mmol) of 3-(3-bromopropoxy)-5-(octadecyloxy)benzoic acid phenylmethyl ester and 1.5 ml (8.74 mmol) of triethyl phosphite was stirred and heated at 150° for 32 hours. Purification by chromatography on 250 g of silica gel gave 3.2 g (60% yield) of 3-[3-(octadecyloxy)-5-(phenylmethoxycarbonyl)phenoxy]propylphosphonic acid diethyl ester as an oil. The structure was confirmed by the nmr spectrum.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][CH2:10][OH:11].CC(C)=O>C(N(CC)CC)C>[OH:11][CH2:10][CH2:9][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: OCCCl
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1CCN(CCO)CC1
Yield: 75 %

Procedure:
N-methylpiperazine (10 g; 100 mmol) and 2-chloroethanol (8.05 g; 100 mmol) are stirred at 100° C. for 4 h. The highly viscous reaction medium is supplemented with 250 ml of acetone and the resulting suspension is neutralized with 15 ml of triethylamine. After filtration of the triethylamine hydrochloride, the solvent is evaporated under reduced pressure. The desired compound is obtained after purification by chromatography on an alumina column (Merck®; Aluminum Oxide 90; 63-200 μm, eluent: ethyl acetate) in the form of a colorless oil. Yield: 75%
Reaction SMILES: CO.C(OC([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([OH:23])[CH2:19][C:20]([NH2:22])=[O:21])=O)C1C=CC=CC=1>[C].[Pd].C(O)(=O)C>[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([OH:23])[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: NC(=O)C[C@@H](O)CCCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: NCCCC[C@H](O)CC(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
Into a mixture of 10 ml of 90% aqueous methanol and 0.01 ml of acetic acid, was dissolved 350 mg (1.19 mmoles) of (S)-7-benzyloxycarbonylamino-3-hydroxyheptanamide. After addition of 50 mg of 5% palladium-carbon, the mixture was stirred under a hydrogen stream for 3 hours at room temperature. After removal of the catalyst by filtration, the filtrate was evaporated to dryness, then dissolved again in a small volume of water, and passed through a column (12 mm in inner diameter) packed with 30 ml of Dowex® 50 W-X4 (H-type). The column was then washed with 90 ml of water and eluted with 0.5 M aqueous ammonia. Fraction Nos. 28 to 34 (each 3 ml in volume) were combined and evaporated to dryness to obtain 201 mg (96% yield) of (S)-7-amino-3-hydroxyheptanamide. [α]D22 -2° (c, 2 water).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:24]=[N:25][C:26]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:28]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:24]=[N:25][C:26]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: C[Si](C)(C)CCOc1ccc(Cl)nn1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(OCC[Si](C)(C)C)nn3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (1 g, 3.20 mmol) and 3-chloro-6-[2-(trimethylsilyl)ethoxy]pyridazine (0.739 g, 3.20 mmol) as the starting materials.
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:23](OCC)=[O:24])[CH2:22][CH2:21][CH2:20]2)=[C:15]([C:28]#[C:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:14]=1>CN(C=O)C.O1CCOCC1>[Cl:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[C:19]1([CH2:22][CH2:21][CH2:20]1)[C:23](=[O:24])[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]2[OH:9]
Reactant: CCOC(=O)C#Cc1cc(Cl)ccc1C1(C(=O)OCC)CCC1
Reactant: ON=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCC2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
Benzaldehyde oxime (174 mg, 1434 μmol) in DMF (7 mL) was added to a stirred suspension of NaH (60% dispersion in mineral oil (57 mg, 1434 μmol)) in dioxane (7 mL) under a N2 atmosphere. The mixture was stirred for approximately 30 minutes before being cooled to 0° C. Ethyl 1-(4-chloro-2-(3-ethoxy-3-oxoprop-1-ynyl)phenyl)cyclobutanecarboxylate (400 mg, 1195 μmol) in DMF (7 mL) was added via syringe, and the reaction was stirred at 0° C. for 1 hour. The reaction was quenched with water, and extracted with EtOAc. The aqueous layer was separated and brought to a pH of about 4 with 10% HCl and extracted again with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give an orange oil. The crude oil was purified by silica flash chromatography (0-20% EtOAc/hexane) to give the desired compound as a white solid (155 mg). MS (m/e)=307.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([O:16]CC3C=CC=CC=3)[CH:13]=[C:12]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:11]=2)=[N:4]1)[CH3:2]>[Pd].C1COCC1.C(O)C>[CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:11]=[C:12]([O:24][C@@H:25]([CH3:29])[CH2:26][O:27][CH3:28])[CH:13]=[C:14]([OH:16])[CH:15]=2)=[N:4]1)[CH3:2]
Reactant: CCn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)COC)c2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCn1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)COC)c2)n1
Reaction time: 16 h

Procedure:
10% Palladium on carbon (1.9 g, 50% wet) was added under argon to N-(1-ethyl-1H-pyrazol-3-yl)-3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]benzamide (19.1 g, 46.7 mmol) in dry THF (100 mL) and ethanol (100 mL). The reaction mixture was degassed, placed under a hydrogen balloon and stirred for 16 hours. The mixture was filtered through diatomaceous earth and the filtrate was evaporated to give a brown oil. The residue was purified by column chromatography on silica, eluting with 40-65% ethyl acetate in hexanes, to give the desired product as a clear oil which crystallised on standing (11.35 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C[O:26][C:27](=O)[CH2:28][C:29]1([CH2:42][CH:43]=O)[CH2:41][CH2:40][C:32]2([O:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][O:33]2)[CH2:31][CH2:30]1.[OH-].[Na+]>O1CCCC1.C(O)C.O.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:43][CH2:42][C:29]3([CH2:41][CH2:40][C:32]4([O:33][CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][O:37]4)[CH2:31][CH2:30]3)[CH2:28][C:27]2=[O:26])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: COC(=O)CC1(CC=O)CCC2(CC1)OCC(C)(C)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@@H](c1ccc(Br)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-1-(4-Bromo-phenyl)-ethylamine (0.17 mL), sodium triacetoxyborohydride (0.25 g), and acetic acid (0.07 mL) are added in the given order to a solution of [3,3-dimethyl-9-(2-oxo-ethyl)-1,5-dioxa-spiro[5.5]undec-9-yl]acetic acid methyl ester (0.35 g) in tetrahydrofuran (5 mL) at room temperature. The resulting mixture is stirred at room temperature overnight. Water (5 mL) and 1 M aqueous NaOH solution (5 mL) are then added and the mixture is stirred for another 20 min. The mixture is extracted with tert-butyl methyl ether, and the combined extract is washed with water and brine. After drying (MgSO4), the solvent is evaporated to give an oil that is treated with a mixture of water and ethanol to precipitate the title compound. Yield: 0.29 g (ca. 70% pure); Mass spectrum (ESI+): m/z=450/452 (Br) [m+H]+.