Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[N:11][CH:12]=1)(=O)=O.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:28](=O)([O-])[O-].[Na+].[Na+].C(O)C>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.O.C1(C)C=CC=CC=1>[C:19]1([C:7]2[CH:8]=[C:9]([C:13]([O:15][CH2:16][CH3:28])=[O:14])[CH:10]=[N:11][CH:12]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cncc(OS(=O)(=O)C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cncc(-c2ccccc2)c1
Yield: 60.2 %

Procedure:
A mixture of methyl 5-trifluoromethanesulfonyloxy-3-pyridinecarboxylate (18.00 g), phenylboronic acid (7.88 g), tetrakis(triphenylphosphine)palladium (3.01 g), sodium carbonate (13.51 g), ethanol (80 ml), water (80 ml) and toluene (500 ml) was refluxed overnight under an argon atmosphere. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 5-phenyl-3-pyridinecarboxylate (8.63 g, yield 60%) as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [F:1][CH:2]([F:36])[CH2:3][N:4]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][C:30](F)=[CH:29][C:28]=1OC)C(=O)C1C=C(C(F)(F)F)N=C(C(F)(F)F)C=1.[CH3:37]C1C=CC=CC=1B(O)O>CCCCCCC.CCOC(C)=O>[F:36][CH:2]([F:1])[CH2:3][NH:4][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:37]
Reactant: Cc1ccccc1B(O)O
Reactant: COc1cc(F)ccc1-c1ccncc1N(CC(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccncc1NCC(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-amine (example 153, intermediate b) and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless solid (93%). MS (ESI): m/z=248.1 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1.C(OP([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:31])=[C:9]([CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:22][N:21]([CH3:26])[N:20]=3)=[CH:15][C:14]=2[O:29][CH3:30])[N:10]=1
Reactant: COc1cc(COc2nn(C)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(C)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Reaction time: 15 h
Yield: 91.5 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazole-4-carbaldehyde (1.50 g), ethyl diethylphosphonoacetate (0.87 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.17 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give ethyl (2E)-3-{3-[(4-([2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-methyl-1H-pyrazol-4-yl)-2-propenoate as colorless crystals (1.60 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-])=[C:10]([CH3:15])[CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:20]#[N:21])(C)C.CN(C)C(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:15])[N:11]=[C:12]([C:20]#[N:21])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1cc(-c2ccc(F)cc2)cc[n+]1[O-]
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2ccc(F)cc2)cc(C#N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 162 %

Procedure:
To a solution of 1.30 g (6.4 mmol) of 4-(4-Fluoro-phenyl)-2-methyl-pyridine 1-oxide in 20 ml of methylene chloride was added dropwise 1.00 ml (8.0 mmol, 1.25 equiv.) of Trimethylsilyl cyanide. Then 0.73 ml (0.86 g, 8.0 mmol, 1.25 equiv.) of Dimethylcarbamoyl chloride was added dropwise over a period of 5 min. After stirring overnight at room temperature, 8 ml of saturated sodium carbonate solution were added. The aqueous phase was extracted twice with 15 ml of methylene chloride. The combined organic phases were washed with 20 ml of brine, dried over magnesium sulfate, and concentrated in vaccuo to yield 2.2 g of a beige solid which was purified by flash chromatography (ethyl acetate/hexane 1:4) to yield the title compound (0.75 g, 55%) as a crystalline white solid, MS (ISP): m/e=213.1 (M+H)+.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:12]Cl>>[OH:4][CH2:3][CH2:2][N:1]([CH2:12][C:11]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:9]([Cl:8])[CH:10]=1)[CH2:5][CH2:6][OH:7]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: OCCNCCO
Product: OCCN(CCO)Cc1ccc(Cl)c(Cl)c1

Procedure:
2-[(2-Hydroxy-ethyl)-(3,4-dichloro-benzyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (4.84 g, 46 mmol) and 3,4-dichlorobenzyl chloride (9.0 g, 46 mmol). Yield 13.8 g (99%); colorless oil; MS: 264.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.Cl[CH2:13][CH2:14][CH2:15]I.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])([O-])=O.[K+].[K+].[CH2:29]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH2:30][CH2:31][CH3:32]>C(#N)C.O>[CH2:29]([CH:33]1[CH2:38][CH2:37][N:36]([CH2:13][CH2:14][CH2:15][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])[CH2:7][CH2:8][CH2:9]2)[CH2:35][CH2:34]1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCC1CCNCC1
Reactant: Cc1cccc2c1NCCC2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCC1CCN(CCCN2CCCc3cccc(C)c32)CC1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
8-Methyl-1,2,3,4-tetrahydroquinoline (125 mg, 0.85 mmol), 1-chloro-3-iodopropane (82 μl, 0.77 mmol) and Cs2CO3 (415 mg, 1.27 mmol) in acetonitrile (2 mL) were shaken at 60° C. for 7 days. KI (140 mg, 0.85 mmol), K2CO3 (117 mg, 0.85 mmol) and 4-butylpiperidine (113 μl, 0.68 mmol) were added and the reaction mixture was shaken at 60° C. for 2 days. Water (5 mL) was added and the product was extracted with ethyl acetate (2×10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by column chromatography (eluent: 20% methanol in ethyl acetate) to yield the title compound. Yield: 45.6 mg (20.4%). HPLC-MS: M+1+=329.5 (UV/MS(%)=99/97). 1H NMR (400 MHz, CDCl3): δ=0.89 (3H, t), 1.18-1.34 (9H, m), 1.70 (2H, broad d), 1.75-1.92 (4H, m), 1.99 (2H, broad t), 2.22 (3H, s), 2.38 (2H, dd), 2.70-2.81 (4H, m), 2.96 (2H, broad d), 3.04-3.10 (2H, m), 6.76 (1H, t), 6.80 (1H, broad d), 6.91 (1H, broad d). 13C NMR (CD3OD): δ 13.2, 17.2, 18.0, 18.1, 22.8, 25.7, 27.7, 28.9, 31.9, 35.7, 36.2, 52.7, 53.9, 56.3, 121.5, 127.1, 128.7, 128.9, 131.0, 148.0.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]=C)[C:10](=[O:16])[CH:9]=[CH:8]2)[CH3:2].O.I([O-])(=O)(=O)=[O:20].[Na+]>O1CCOCC1.[Cl-].[Na+].O.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[CH2:1]([C:3]1[C:4]([F:17])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH:14]=[O:20])[C:10](=[O:16])[CH:9]=[CH:8]2)[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCn1c(=O)ccc2ncc(F)c(CC)c21
Agent: O=[Os](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1c(F)cnc2ccc(=O)n(CC=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
8-ethyl-7-fluoro-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one (0.181 g, 0.781 mmol) was dissolved in 1,4-dioxane (4.0 mL) and water (3.5 ml) at rt under argon. Then sodium periodate (0.418 g, 1.95 mmol) was added followed by osmium tetroxide (0.175 mL of 4% aqueous solution). After 10 mins a white precipitate came out of solution, further addition of water (2 ml) was required to re-dissolve everything. After the reaction had been left stirring at rt overnight, it was then diluted with brine (20 ml) and EtOAc (20 ml). The aqueous was then separated and washed a further with EtOAc (3×20 ml). The organic layers were then combined, dried using sodium sulphate, filtered and solvent removed to give the crude product as a yellow solid (0.168 g).
Reaction SMILES: [Si:1]([O:18][C@@H:19]([CH3:23])[C:20]([OH:22])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:57]([CH2:60][CH2:61][CH2:62][C:63]1([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[NH:67][N:66]=[C:65]([C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=2[F:75])[S:64]1)=[N+:58]=[N-:59]>C(#N)C>[N:57]([CH2:60][CH2:61][CH2:62][C@:63]1([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[N:67]([C:20](=[O:22])[C@@H:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:23])[N:66]=[C:65]([C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=2[F:75])[S:64]1)=[N+:58]=[N-:59]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Reactant: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.1 %

Procedure:
To a solution of (S)-2-(t-butyldiphenylsilyloxy)propanoic acid (339 mg, 1.09 mmol) in acetonitrile (6 mL) was added HATU (550 mg, 1.45 mmol) followed by DIEA (0.378 mL, 2.17 mmol). After stirring at room temperature for 15 minutes, a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (260 mg, 0.72 mmol) in acetonitrile (4 mL) was added. After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO3 (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The brown oil was chromatographed (9:1 hexanes/ethyl acetate) to provide the less polar diastereomer, (S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (121 mg) and the more polar diastereomer, (S)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (175 mg) as pale yellow oils. Absolute stereochemistry was assigned by examination of a protein:inhibitor co-crystal structure of Eg5 and (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[N:7]=[C:6]1[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=2[C:34]2[CH:39]=[CH:38][C:37](F)=[CH:36][CH:35]=2)[CH2:23][CH2:22]1.CC1(C)C(C)(C)OB(C2C=CC([C:54]([O:56][CH3:57])=[O:55])=CC=2)O1>>[NH2:33][C:29]1[C:28]([C:34]2[CH:39]=[CH:38][C:37]([C:54]([O:56][CH3:57])=[O:55])=[CH:36][CH:35]=2)=[C:27]([N:24]2[CH2:23][CH2:22][CH:21]([C:6]3[N:5]([CH2:4][CH2:3][N:2]([CH3:41])[CH3:1])[CH:9]=[C:8]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=4)[N:7]=3)[CH2:26][CH2:25]2)[N:32]=[CH:31][N:30]=1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COC(=O)c1ccc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN(C)C)CC2)cc1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine using methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate instead of 4-fluorophenyl boronic acid. LC-MS: (M+1=612, obsd.=612).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[O:7][C:8](/[CH:11]=[CH:12]/[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][CH:10]=1)[OH:5].[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>C(Cl)Cl>[CH:13]1(/[CH:12]=[CH:11]/[C:8]2[O:7][C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:21](=[O:22])[C:20]([F:27])([F:26])[F:19])=[CH:10][CH:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NCCC(O)c1ccc(/C=C/C2CCCCC2)o1
Reactant: CCOC(=O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCC(O)c1ccc(/C=C/C2CCCCC2)o1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(E)-3-amino-1-(5-(2-cyclohexylvinyl)furan-2-yl)propan-1-ol (0.25 g, 1.0 mmol) was dissolved in CH2Cl2 (5 mL) and ethyl trifluoroacetate (0.5 mL) was added. The reaction mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. Purification by flash chromatography (10%-50% EtOAc—hexanes gradient) gave (E)-N-(3-(5-(2-cyclohexylvinyl)furan-2-yl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a colorless oil. Yield (0.26 g, 75%). (E)-N-(3-(5-(2-Cyclohexylvinyl)furan-2-yl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (0.15 g, 0.434 mmol) was dissolved in MeOH:H2O (3:1, 8 mL) and K2CO3 (0.13 g, 0.94 mmol) was added. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. Flash chromatography purification (2%-16% 7N NH3/MeOH—CH2Cl2 gradient) gave Example 14 as a light yellow oil. Yield (0.025 g, 23%); 1H NMR (400 MHz, CD3OD) δ 6.00-6.40 (m, 4H), 4.64-4.74 (m, 1H), 2.70-2.80 (m, 2H), 2.01-2.14 (m, 1H), 1.90-2.00 (m, 2H), 1.50-1.80 (m, 5H), 1.10-1.40 (m, 5H); RP-HPLC tR=10.06 min; ESI-MS m/z 232.2 [M−H2O+H]+.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([O:22][CH3:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[CH2:24]([I:27])[CH:25]=[CH2:26]>CN(C)C=O>[I-:27].[CH2:24]([N@+:2]1([CH3:1])[CH2:3][CH2:4][C@:5]23[C:15]4[C:16]5[O:21][C@H:6]2[C:7](=[O:8])[CH2:9][CH2:10][C@@:11]3([O:22][CH3:23])[C@H:12]1[CH2:13][C:14]=4[CH:19]=[CH:18][C:17]=5[OH:20])[CH:25]=[CH2:26]
Reactant: CO[C@@]12CCC(=O)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(C)[C@@H]2C5
Reactant: C=CCI
Solvent: CN(C)C=O
Product: C=CC[N@+]1(C)CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(OC)[C@H]1C5
Product: [I-]

Procedure:
A solution of 14-O-methyloxymorphone (Schmidhammer et al., J. Med. Chem. 1984, 27, pp. 1575-1579) (210 mg, 0.67 mmol) and allyl iodide (0.28 ml, 3.35 mmol) was stirred in 5 ml N,N-dimethylformamide for 7 days at 40° C. (bath temperature) and then evaporated down. The evaporation residue (484 mg of brown oil) was purified using column chromatography (silica gel; CH2Cl2/MeOH (250:5->250:12)). The evaporation residue (134 mg) was again purified using column chromatography (silica gel; CH2Cl2/MeOH (250:4.5)). Evaporation residue 77 mg (27%) of amorphous compound 43. Fp. >140° C.; IR (KBr): 1724 (CO) cm−1; 1H-NMR (DMSO-d6): δ 9.57 (s, C3-OH), 6.68 (s, 2 arom. H), 6.28-6.08 (m, 1 olef. H), 5.75-5.63 (m, 2 olef. H), 4.95 (s, C5-H), 3.42 (s, CH3O), 3.05 (s, +NCH3, equatorial); MS (CI): m/z 356 (M+).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH:24]=O.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][CH:21]=[C:20]2[CH2:24][NH:6][CH3:5]
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: O=Cc1c[nH]c2c(F)cccc12
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1c[nH]c2c(F)cccc12
Yield: 90 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 7-fluoro-1H-indole-3-carboxaldehyde (0.5 g, 3.1 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.5 g, 90%) was prepared as a viscous oil: MS (ES) m/e 179 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][N:7]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([N:57]1[CH:61]=[C:60]([CH2:62][C:63]2[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=2)[N:59]=[CH:58]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:59]2[C:60]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=3)=[CH:61][N:57]=[CH:58]2)=[CH:8][N:7]=1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: OCc1ccc(-c2cccs2)nc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-c3cccs3)nc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(thien-2-yl)-5-hydroxymethylpyridine (255 mg, 1.33 mmol) and diisopropylethylamine (0.464 mL, 2.66 mmol) in dichloromethane (7 mL) at -78° C. is added trifluoromethane-sulfonic anhydride (0.224 mL, 1.33 mmol) and the mixture stirred at -78° C. for 1 hour. To this mixture is added a solution of 1-trityl-4-(4-cyanobenzyl)-imidazole (566 mg, 1.33 mmol) in dichloromethane (5 mL). The mixture is allowed to warm to ambient temperature and stirred for 2 hours. The solvent is evaporated in vacuo. The residue is dissolved in methanol (50 mL), heated at reflux for 1 hour, and the solvent is evaporated in vacuo. The residue is partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer is dried, (Na2SO4) and the solvent evaporated in vacuo. The residue is chromatographed to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=1[NH2:14].C(O)(=O)C>O>[F:11][C:12]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=1[NH:14][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(F)cc1F
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of (7.9 g., 0.05 mole) 2-chloro-3-nitropyridine and 12.9 g. (0.10 mole) of 2,4-difluoroaniline was purged with nitrogen and heated in an oil bath to 110° C. when the temperature rose spontaneously to 135° C. Heating was continued to 145° C. when a second spontaneous temperature rise occurred requiring temperature control with ice. The maximum internal temperature was 185° C. After slight cooling, 40 ml. of acetic acid and 60 ml. of water was added. After stirring one hour the crystalline precipitate was collected (11.1 g., m.p. 110° C.) and recrystallized from hexane to give 2-(2,4-difluoroanilino)-3-nitropyridine, m.p. 112°-114° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[O:10]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]3[N:21]=[C:22]([NH2:24])[N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)=[CH:11]1.CC(C)([O-])C.[Na+].CCOCC>C1COCC1>[O:10]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]3[N:21]=[C:22]([NH:24][C:1](=[O:9])[C:2]4[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=4)[N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)=[CH:11]1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
A solution of nicotinic acid (74 mg, 0.6 mmol, 1.2 eq.) and 1,1-carbonyldiimidazole (122 mg, 0.75 mmol, 1.5 eq.) in dry THF (1 mL) was stirred for 45 min. at rt. In parallel, a solution of 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 100 mg; 0.50 mmol; 1.0 eq.) and sodium tert-butoxide (96 mg, 1.0 mmol, 2.0 eq.) in dry THF (2 mL) was stirred for 45 min. at rt. The two solutions were then combined and the reaction mixture was stirred overnight at rt. Et2O was then added and the precipitate obtained was filtered, washed with Et2O, THF, a 5N solution of NaOH and water. It was resuspended in an acidic aqueous solution (pH 1) and filtered to give the title compound as a white powder (52.4 mg, 31%). HPLC, Rt: 1.98 min. (purity 95.1%). LC/MS, M+(ESI): 306.1, M−(ESI): 304.1.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([O:17][CH3:18])[C:10]=1[F:19])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:20](OC(=O)C)(=O)C.C(OCC)(OCC)OCC.[F:37][C:38]([F:42])([F:41])[CH2:39][NH2:40]>>[F:37][C:38]([F:42])([F:41])[CH2:39][NH:40][CH:20]=[C:3]([C:2](=[O:1])[C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([O:17][CH3:18])[C:10]=1[F:19])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: NCC(F)(F)F
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC)c1F
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)C(=CNCC(F)(F)F)C(=O)c1cc(F)c(F)c(OC)c1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2.00 g (5.79 mmol) of ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate (for preparation see Journal of Medicinal Chemistry (1995), 38 (22), 4478-87) are stirred under reflux in 3.8 ml (4.14 g, 40.55 mmol) of acetic anhydride and 4.82 ml (4.29 g, 28.96 mmol) of triethyl orthoformate for 2 h. The solvent is then removed completely on a rotary evaporator and the residue is dissolved in 10 ml of ethanol. 1.03 g (10.43 mmol) of 2,2,2-trifluoro-1-aminoethane are added dropwise to the ice-cooled solution. The mixture is brought to room temperature and stirred at that temperature overnight. For the work up, the solvent is removed and the residue is reacted further as a crude product without purification steps (yield assumed to be quantitive).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
L-Phenylalanine (5 g, 30 mmol) was dissolved in a solution (200 ml) containing equal proportions of tetrahydrofuran and 5% NaHCO3, and chilled to 0° C. Benzyl chloroformate (4.7 ml, 33 mmol) was dissolved in tetrahydrofuran (10 ml) and added slowly to the amino acid solution over a period of 1 hour. The pH was continually adjusted to 8.5 by the addition of 5% Na2CO3 and the reaction was allowed to proceed at room temperature overnight. The organic solvent was removed under reduced pressure and the resulting aqueous solution was poured slowly into chilled, concentrated HCl (50 ml). The product precipitated and was extracted into ethyl acetate (200 ml). It was washed with 5% NaHSO4 and dried over magnesium sulphate. Recrystallisation was from ethyl acetate/hexane. Yield 8.29 g (91%), m.p. 83°-83° C. (Lit. 82°-84° C., Berger et al., 1973). The product was homogeneous as judged by tlc in chloroform/methanol (4:1) (Rf 0.500) or chloroform/methanol (1:1) (Rf 0.364).