Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][N:5]([C:18](=[O:31])[CH:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]C=C)[CH2:6][C:7]([C:9]([CH3:17])([CH3:16])[O:10][SiH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH2:8].CS(C)=O>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[CH2:4][N:5]1[CH2:6][C:7]([C:9]([CH3:16])([CH3:17])[O:10][SiH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:8][CH2:20][CH:19]([NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C:18]1=[O:31]
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)N(CC(=C)C(C)(C)O[SiH2]C(C)(C)C)CC(=O)OC
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)CN1CC(C(C)(C)O[SiH2]C(C)(C)C)=CCC(NC(=O)OC(C)(C)C)C1=O
Reaction time: 12 h
Yield: 96 %

Procedure:
Super Grubbs catalyst (2 g) is added to a solution {(2-tert-butoxycarbonylamino-pent-4-enoyl)-[2-(tert-butyl-dimethyl-silanyloxymethyl)-allyl]-amino}-acetic acid methyl ester, 16, (4.1 g, 8.7 mmol) in CH2Cl2(100 mL). The solution is refluxed for 1 hour then DMSO (10 mL) is added and stirring is continued for another 12 hours at room temperature. The solvent is removed in vacuo and the residue purified over silica (EtOAc/hexane) to afford 3.7 g (96% yield) of the desired product. 1H NMR (CDCl3) δ 5.80–5.78 (d, J=6.3 Hz, 1H), 5.65 (bs, 1H), 5.03–4.96 (m, 1H), 4.56–4.48 (m, 2H), 3.98 (s, 2H), 3.98–3.92 (d, J=17.4 Hz, 1H), 3.73 (s, 3H), 3.44–3.38 (d, J=17.7, 1H), 2.74–2.67 (d, d, J=18, 3.3 Hz, 1H), 2.30–2.18 (m, 1H), 1.45 (s, 9H), 0.89 (s, 9H), 0.06 (s, 6H); 13C (CDCl3) δ 172.9, 169.6, 155.2, 135.6, 124.6, 79.7, 66.9, 60.5, 52.4, 50.0, 49.8, 47.6, 33.1, 28.5, 26.0, 18.4,14.4, −5.0; MS 442 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[C:11](Cl)(=[O:15])[C:12]([CH3:14])=[CH2:13]>C(#N)C.N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1)(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc2[nH]nnc2c1
Solvent: CC#N
Solvent: c1ccncc1
Product: C=C(C)C(=O)Nc1ccc2[nH]nnc2c1
Reaction time: 0.5 h

Procedure:
After 26.8 g of 5-aminobenzotriazole was dissolved in a mixture of acetonitrile (300 ml) and pyridine (40 ml), 46.5 g of methacrylic acid chloride was added dropwise. The resulting solution was concentrated and 200 ml of a 10% aqueous solution of sodium hydroxide was added. After the mixture was agitated for 30 minutes, it was neutralized with dilute hydrochloric acid and the end compound was obtained as a solid precipitate in an amount of 27.3 g (yield, 6.7%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][CH:7]([C:9]([OH:11])=O)[CH2:6][CH2:5]1.C(Cl)(=O)[C:13]([Cl:15])=O>ClCCl.CN(C)C=O>[Cl:15][CH2:13][C:9]([CH:7]1[CH2:6][CH2:5][CH:4]([CH2:3][O:2][CH3:1])[O:8]1)=[O:11]
Reactant: COCC1CCC(C(=O)O)O1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCC1CCC(C(=O)CCl)O1
Temperature: 0 °C

Procedure:
A solution of (2RS,5SR)-5-methoxymethyltetrahydrofuran-2-carboxylic acid (3.1g) in dichloromethane (50ml) was treated with oxalyl chloride (2.68ml) and dimethylformamide (1 drop). The mixture was stirred for 1h and heated to reflux for 10 mins. The solvent was evaporated and then dichloromethane was evaporated from the residue twice. The product was dissolved in dichloromethane (100ml) and the solution cooled in an ice bath. Diazomethane was then passed into the solution as described in Example 14(a). When the addition was complete the mixture was stirred at 0° C. for 0.5h and then hydrogen chloride gas was passed into the solution until all the diazoketone had been consumed. The solution was washed with brine, dried over magnesium sulphate and evaporated. The title compound (2.44g) was isolated by column chromatography using gradient elution (silica gel, 4:1 going to 1:1 hexane : ethyl acetate); vmax (film) 1740cm-1 ; δH (CDCl3) 1.6-2.35 (4H,m), 3.30-3.75 (2H,m), 3.37 (3H,s) and 4.05-4.75 (4H,m).
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[C:10]([Cl:11])=[C:9]([SH:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17].[O:23]1[CH:25]([CH2:26][CH3:27])[CH2:24]1.CCOC(C)=O>C1COCC1>[OH:23][CH:25]([CH2:26][CH3:27])[CH2:24][S:12][C:9]1[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:17])([F:18])[F:19])=[C:5]([Cl:4])[C:10]=1[Cl:11]
Reactant: CCC1CO1
Reactant: C[C@@](O)(C(=O)Nc1ccc(S)c(Cl)c1Cl)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)CSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium methoxide (0.075 g) was added to a stirred solution of (R)-N-[2,3-dichloro-4-mercaptophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 35) (0.44 g) in anhydrous THF (10 ml). The reaction mixture was stirred at ambient temperature for 5 minutes and 1,2-epoxybutane (0.11 ml) was added. The mixture was heated under reflux for 2 hours and allowed to cool to ambient temperature. EtOAc (150 ml) was added and the mixture washed with brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified on a 20 g silica Mega Bond Elut column eluting with 1-40% EtOAc/isohexane to give the title compound (0.259 g) as an orange solid. NMR: 0.88 (t, 3H), 1.35-1.49 (m, 1H), 1.58 (s, 3H), 2.97-3.08 (m, 1H), 3.53-3.62 (m, 1H), 5.00 (d, 1H), 7.42 (d, 1H), 7.77 (d, 1H), 9.79 (brs, 1H); m/z: 404.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[C:22](O)(=O)[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>P(Cl)(Cl)(Cl)=O>[CH3:15][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[N:5]=[C:4]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:3]=[C:2]3[C:7]=2[NH:8][C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[N:1]3)[CH2:10][CH2:11]1
Reactant: O=C(O)c1ccncc1
Reactant: CN1CCN(c2nc(-c3ccccc3)nc(N)c2N)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(c2nc(-c3ccccc3)nc3nc(-c4ccncc4)[nH]c23)CC1
Yield: 52.6 %

Procedure:
To 80 ml of phosphorus oxychloride are added 4 g of 4,5-diamino-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine and 1.7 g of isonicotinic acid, and the mixture is refluxed with heating for 6 hours under stirring. The reaction solution is concentrated and 700 ml of water is added to the residual oil. The solution is neutralized with an ammonia solution and the crystals precipitated are filtered, and then washed with water. Recrystallization from a mixture of chloroform and methanol (2:1) gives 2.7 g of 6-(4-methyl-1-piperazinyl)-2-phenyl-8-(4-pyridyl)purine, melting at 333°-337° C.
Reaction SMILES: C1N=[C:5]2[N:7]([C@@H:10]3O[C@H:13](COP(OP(OP(O)(O)=O)(O)=O)(O)=O)[C@@H:12](O)[CH2:11]3)C=N[C:4]2=[C:3](N)[N:2]=1.P(OC[C@H]1O[C@@H]([N:50]2C3N=C(N)NC(=O)C=3N=C2)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.P(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.OP(=O)(OC[C@H]1O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1O)OP(=O)(OP(=O)(O)O)O>>[NH2:50][CH2:13][CH2:12][CH2:11][CH2:10][NH:7][CH2:5][CH2:4][CH2:3][NH2:2]
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Product: NCCCCNCCCN

Procedure:
0.2 mM ea dATP, dGTP, dCTP, dTTP
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH2:25])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15].[Br:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:28]=1[C:29](Cl)=[O:30].C(N(C(C)C)CC)(C)C>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH:25][C:29]([C:28]1[C:32]([Cl:36])=[CH:33][CH:34]=[CH:35][C:27]=1[Br:26])=[O:30])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: O=C(Cl)c1c(Cl)cccc1Br
Reactant: NCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1c(C(=O)NCC(O)(CNC(=O)c2c(Cl)cccc2Br)C(F)(F)F)cnn1-c1ccc(F)cc1
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 5-amino-N-[2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (250 mg, 0.69 mmol) in tetrahydrofuran (2 ml) was added 2-bromo-6-chlorobenzoyl chloride (192.7 mg, 0.76 mmol) followed by diisopropylethylamine (178 mg, 1.38 mmol). The reaction was left stirring under nitrogen overnight. LC-MS analysis showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was redissolved in dichloromethane and washed with 2M hydrochloric acid followed by water. The organic layer was concentrated in vacuo to give the title compound (280 mg).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[C:19]([S-:21])#[N:20].[K+]>C(O)C.O.Cl>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:5]2[CH:4]=[CH:3][N:20]=[C:19]2[SH:21])=[CH:10][CH:11]=1
Reactant: N#C[S-]
Reactant: COc1ccc(CCCNCC(OC)OC)cc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CCCn2ccnc2S)cc1

Procedure:
A solution of 3.62 g (.014 mole) of N-[3-(4-methoxyphenyl)propyl]aminoacetaldehyde dimethyl acetal and 1.4 g (.0144 mole) of KSCN in 20 ml of ethanol, 5 ml of H2O and 2 ml of concentrated HCl was refluxed for five hours. Fifty ml of H2O was added, the mixture was cooled and a solid was filtered, washed with H2O and dried. Recrystallization from ethanol gave 1-[3-(4-methoxyphenyl)propyl]-2-mercaptoimidazole, 2.4 g (69%), mp 108-109°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]([O:20]CC)=O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.O.[NH2:24][NH2:25]>C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][CH2:17][C:18]([NH:24][NH2:25])=[O:20])=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: CCOC(=O)CCc1ccc2c(cnn2C2CCCCO2)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CCc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Yield: 99.5 %

Procedure:
To a stirred solution of ethyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)propanoate (0.59 g, 1.951 mmol) in ethanol (5 mL) was added hydrazine hydrate (0.306 mL, 9.76 mmol) and the reaction was heated at 80° C. overnight. The solid which formed was filtered and dried to afford 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl) propanehydrazide (0.56 g, 82%), used without further purification. 1HNMR: 400 MHz, DMSO-d6: δ 1.58-1.59 (m, 2H), 1.92-1.96 (m, 1H), 1.97-2021.00 (m, 1H), 2.34-2.42 (m, 3H), 2.90-2.92 (m, 2H), 3.72-3.76 (m, 1H), 3.86-3.89 (m, 1H), 4.14 (s, 4H), 5.79-5.79 (m, 1H), 7.25-7.26 (m, 1H), 7.54 (s, 1H), 7.62 (d, J=8.80 Hz, 1H), 8.01 (s, 1H), 8.94 (s, 2H). LCMS: RT 0.64 min; LCMS (ES-API), m/z 205 (M-THP).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH2:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>CN1C(=O)CCC1>[C:32]([O:31][C:30](=[O:36])[NH:29][C@@H:27]([CH3:28])[CH2:26][NH:25][C:9]1[N:8]=[C:7]([C:6]2[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:3][C:2]=2[Br:1])[CH:12]=[CH:11][N:10]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: C[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H](CNc1nccc(-c2c(Br)nc(C3CC3)n2COCC[Si](C)(C)C)n1)NC(=O)OC(C)(C)C
Temperature: 110 °C

Procedure:
A mixture of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (5.50 g, 12.8 mmol), (S)-tert-butyl 1-aminopropan-2-ylcarbamate (SM-1, 2.68 g, 15.4 mmol), diisopropylethylamine (2.68 mL, 15.4 mmol) and sodium carbonate (2.71 g, 25.6 mmol) in NMP (8 mL) was heated with 110° C. oil bath for 3.5 hours and LCMS analysis of an aliquot indicated reaction completion with desired product. The reaction was allowed to cool to ambient temperature, then partitioned between EtOAc (20 mL) and water (60 mL). The EtOAc layer was washed with water (60 mL), dried (Na2SO4), and concentrated to a light yellow foam (6.89 g, 12.1 mmol). A small portion of material was further purified by flash chromatography (SiO2, EtOAc in heptane): LCMS(m/z) 567.3 (MH+), tR=1.03 minutes; 1H NMR (CDCl3, 300 MHz) δ-0.09 (s, 9H), 0.80 (t, J=8.2 Hz, 2H), 0.98-1.07 (m, 2H), 1.10-1.18 (m, 2H), 1.21 (t, J=6.5 Hz, 3H), 1.40 (s, 9H), 1.91-2.08 (m, 1H), 3.41 (t, J=8.2 Hz, 2H), 3.44-3.59 (m, 2H), 3.82-4.01 (m, 1H), 4.65-4.87 (m, 1H), 5.41-5.61 (m, 1H), 5.78-5.99 (m, 2H), 7.10 (d, J=5.0 Hz, 1H), 8.33 (d, J=5.2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][NH:5][CH2:6][C:7]1[S:8][C:9]([CH3:12])=[CH:10][CH:11]=1.C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CCOC(C)=O>[CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][N:5]([CH2:6][C:7]1[S:8][C:9]([CH3:12])=[CH:10][CH:11]=1)[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1ccc(C)s1)OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(CN(Cc1ccc(C)s1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Crude (2,2-dimethyloxy-ethyl)-(5-methyl-thiophen-2-ylmethyl)-amine (1) (43.41 g ˜75% pure, 0.15 mol) was dissolved in EtOAc (150 mL) resulting in a yellow solution. Triethylamine (22 mL, 0.16 mol) was added. The mixture was cooled to 0° C. in ice bath. p-Toluenesulfonyl chloride (29.68 g, 0.16 mol) was added in small portions keeping the temperature below 15° C. After addition was complete the mixture was left in ice bath and allowed to slowly warm to room temperature and stirred for 20 hrs. The milky-yellow mixture was diluted with EtOAc (300 mL) and washed with water (2×400 mL), 1 M HCl (2×400 mL), water (1×400 mL), sat NaHCO3 (1×400 mL), and brine (1×400 mL), dried (MgSO4) and condensed to provide the title compound as a reddish-yellow liquid, 50.56 g. Product was not purified.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][CH3:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CCC[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (5.0 g) in dimethyl sulfoxide (80 mL) were added L-norvaline (4.52 g) and cesium carbonate (13.6 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 8.12 g, 100%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1([C:55]2[CH:56]=[C:57]([CH:59]=[CH:60][CH:61]=2)[NH2:58])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>CN(C=O)C>[N:49]1([C:55]2[CH:56]=[C:57]([NH:58][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=[CH:60][CH:61]=2)[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(N2CCOCC2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 43 %

Procedure:
DIEA (0.028 mL, 0.160 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.030 g, 0.146 mmol) and HATU (0.061 g, 0.160 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-morpholin-4-ylaniline (0.026 g, 0.146 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 43% yield: LCMS (ESI) m/z 367 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([O:18][C:19]4[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[N:13]=3)=[C:10](C3C=CC(F)=CC=3)[N:9]=[CH:8]2)[CH2:3][CH2:2]1.[C:35](O)([C:37]([F:40])(F)F)=O>>[NH:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([O:18][C:19]4[CH:20]=[CH:21][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:23][CH:24]=4)[N:13]=3)=[C:10]([O:18][C:19]3[CH:24]=[CH:35][C:37]([F:40])=[CH:21][CH:20]=3)[N:9]=[CH:8]2)[CH2:5][CH2:6]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)c1ccc(Oc2nccc(-c3c(-c4ccc(F)cc4)ncn3C3CCNCC3)n2)cc1
Product: CC(C)c1ccc(Oc2nccc(-c3c(Oc4ccc(F)cc4)ncn3C3CCNCC3)n2)cc1
Reaction time: 0.5 h

Procedure:
1-(Piperidin-4-yl)-4-(4-fluorophenyl)-5-[2-(4-isopropylphenoxy)pyrimidin-4-yl]imidazole. The product of the preceding example was combined with TFA, stirred 30 min and the TFA was removed in vacuo. The residue was dissolved in EtOAc (75 mL) and washed with 10% aq NaOH, H2O, satd aq NaCl, dried (Na2SO4) and concentrated. The resulting residue was crystallized from EtOAc/hexane to afford 44 mg of the title compound as a white solid. ES+MS m/z=458 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[C:7]([CH:10]=1)[C:8]#[N:9])=O.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1>N1C=CC=CC=1>[C:8]([C:7]1[CH:10]=[C:3](/[CH:1]=[CH:17]/[C:18]([OH:20])=[O:19])[CH:4]=[CH:5][C:6]=1[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)#[N:9]
Reactant: N#Cc1cc(C=O)ccc1-n1cncn1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: N#Cc1cc(/C=C/C(=O)O)ccc1-n1cncn1

Procedure:
2.05 g (10.3 mmol) of 5-formyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (lit.: WO-A-2008/019760), 1.60 g (16.6 mmol) of malonic acid and 176 mg (2.07 mmol) of piperidine were stirred in 20 ml of pyridine at 80° C. for 48 hours. The pyridine was distilled off under reduced pressure. The residue was added to ice-water and adjusted to pH 1 with concentrated hydrochloric acid. The aqueous phase was extracted repeatedly with ethyl acetate and dried over sodium sulphate, and the solvent was distilled off under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.O.[Pd]>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([OH:20])=[O:19])=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
The Suzuki coupling was carried out according to the method of Dyer et al. (2001) Tetrahedron Letters 42:1765-1767. Commercially available 4-(trifluoromethyl)phenylboronic acid (15 g, 78.7 mmol) and 3-bromobenzoic acid (15.1 g, 75 mmol) were suspended in i-PrOH:water (1:4, 72 mL). 10% Pd/C (1.5 g) was added followed by aqueous Na2CO3 (39 mL, 20% by wt.). The resulting mixture was heated at 70° C. for 4 hours. The precipitate was filtered and rinsed with 20% aqueous Na2CO3 solution. The filtrate was diluted with water and acidified to pH=2. The white solid was filtered and dried in vacuo to afford 2.1 (19.69 g).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:16][CH2:17][CH2:18][CH2:19]Br.CCOC(C)=O>C1COCC1>[Br:16][CH2:17][CH2:18][CH2:19][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: BrCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: BrCCCn1c2ccccc2c2ccccc21
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 115.9 %

Procedure:
A 250-mL round-bottomed flask was charged with a solution of 9H-carbazole (5 g, 29.94 mmol, 1.00 equiv) in THF (200 mL). To this was added NaH (1.8 g, 75.00 mmol, 1.50 equiv) in small portions at and allowed to stir for 30 minutes. To the mixture was added 1,3-dibromopropane (18 g, 89.55 mmol, 3.00 equiv) at −10° C. and warmed up to 30° C. in an oil bath for 30 minutes. The reaction progress was monitored by TLC (EtOAc:PE=1:5). Upon completion, the reaction was then quenched by the addition of water (100 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). Combined organic layers were washed with brine (3×50 mL), dried over anhydrous sodium sulfate. Solids were filtered off and the mixture was concentrated on a rotary evaporator affording 9-(3-bromopropyl)-9H-carbazole as yellow solid (10 g).
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH:15]([OH:30])[CH2:16][S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OCC(O)CSCCCCCCCCCCCC)CCCCCCCCCCCCCCC.[CH3:65][C:66]1[C:71]([CH3:72])=[C:70]([OH:73])[C:69]([C:74]([CH3:77])([CH3:76])[CH3:75])=[CH:68][C:67]=1[CH2:78][CH2:79][C:80](OC)=[O:81].CC1C=C(CCC(OC)=O)C=C(C(C)(C)C)C=1O>>[CH3:65][C:66]1[C:71]([CH3:72])=[C:70]([OH:73])[C:69]([C:74]([CH3:76])([CH3:77])[CH3:75])=[CH:68][C:67]=1[CH2:78][CH2:79][C:80]([O:30][CH:15]([CH2:16][S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:14][S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:81]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C
Reactant: CCCCCCCCCCCCSCC(O)CSCCCCCCCCCCCC
Agent: CCCCCCCCCCCCCCCCOCC(O)CSCCCCCCCCCCCC
Agent: COC(=O)CCc1cc(C)c(O)c(C(C)(C)C)c1
Product: CCCCCCCCCCCCSCC(CSCCCCCCCCCCCC)OC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C

Procedure:
When an equivalent amount of 1,3-bis(n-dodecylthio)-2-propanol was substituted for 1-n-hexadecyloxy-3-n-dodecylthio-2-propanol and an equivalent amount of methyl 3-(2,3-dimethyl-5-tert-butyl-4-hydroxyphenyl)propionate substituted for methyl 3-(3-methyl-5-tert-butyl-4-hydroxyphenyl)propionate in Example 1, the above-named ester was obtained as a viscous oil. (Compound 4)