Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SeH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[Na+].I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]I.CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.C1(C)C=CC=CC=1>[C:1]1([Se:7][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Ic1ccccc1
Reactant: [SeH]c1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: Cc1ccccc1
Product: c1ccc([Se]c2ccccc2)cc1
Reaction time: 24 h

Procedure:
In a similar manner, the cross-coupling reaction between aryl iodides and phenyl selenol was initially investigated using 10 mol % CuI/neocuproine with NaOt-Bu as the base and toluene as the solvent. Using this protocol, in 24 h, the reaction between iodobenzene and phenyl selenol was complete. If in the reaction protocol neocuproine was replaced by phenanthroline, diphenyl selenide was obtained in a lower yield (70% by GC). Moreover, the reaction with the well-defined complex Cu-(neocuproine)(PPh3)Br showed complete conversion to the product after the same period of time. Use of CuI/neocuproine as catalyst, instead of the well-defined Cu(neocuproine)(PPh3)Br, dispenses with the need to synthesize the complex and the results are comparable. The effect of the base on such reactions (see Table 4).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:14]=[C:13]([CH2:15][N:16]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 110.5 %

Procedure:
To a solution of ethyl [2-methyl-4-({pentyl[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)phenoxy]acetate (54 mg, 0.11 mmol) in MeOH (2 mL) and THF (2 mL) at room temperature was added 2M NaOH (1 mL, 2 mmol). The resultant mixture was stirred for 1 h and then the solvents were removed in vacuo. The residue was partitioned between CH2Cl2 (2×10 mL) and 2M HCl (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed, affording the title compound as a white solid (59 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH:8]=O)=[CH:4][CH:3]=1.[ClH:12].Cl.[NH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]1[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][C:27]=2[CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:30]=1)(=[O:20])=[O:19].CCN(CC)CC.[BH4-].[Na+]>CO>[ClH:1].[ClH:12].[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[C:22]3[CH:23]=[CH:24][N:25]=[CH:26][C:27]=3[CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:30]=2)(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: O=CCOc1ccc(Cl)cc1
Reactant: NCCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=S(=O)(NCCNCCOc1ccc(Cl)cc1)c1cc(-c2ccccc2)cc2cnccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A 1.96 mL of (4-chloro-phenoxy)-acetaldehyde stock solution (˜0.46 mmol) is added to a stirred mixture of 7-phenyl-isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide di-hydrochloride (152 mg, 0.380 mmol), 4 Å molecular sieve (300 mg) and NEt3 (0.212 mL, 1.52 mmol) in anhydrous CH3OH (4 mL) at ambient temperature under nitrogen. The resultant mixture is stirred for 16 hours. Then the mixture is cooled to 0° C. before it is treated with powdered sodium borohydride (43.1 mg, 1.14 mmol). The mixture is stirred at 0° C. for 1 hour, then at ambient temperature for another 1 hour. After filtration and subsequent concentration in vacuo, the crude product is chromatographed on silica (gradient 5-25% CH3OH in EtOAc) to give 104 mg of the free amine product as a gum (0.216 mmol, 57% yield). The free amine (102 mg, 0.212 mmol) is dissolved in EtOAc (15 mL) and treated dropwise with 1N HCl/Et2O solution (0.635 mL) with stirring under nitrogen. The white suspension is stirred for 15 minutes, filtered and dried under vacuum at 60° C. to give 112 mg (0.202 mmol, 95% yield) of the title compound as a white powder. ESIMS: m/z 482 [(M+H)+, 35Cl], 484 [(M+H)+, 37Cl].
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH2:6][CH:5]2[C:11]([O:13]C)=O)[CH:2]=[CH2:3].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(Cl)Cl>[CH2:15]([NH:22][C:11]([CH:5]1[CH2:6][CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CCC12C=CC(CC1C(=O)OC)C2
Reactant: NCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C=CCC12C=CC(CC1C(=O)NCc1ccccc1)C2

Procedure:
9.6 g of methyl allylbicyclo[2.2.1]hept-5-ene-2-carboxylate are mixed with 30 ml of benzylamine and 1 g of ammonium chloride, and the mixture is heated for 3 hours under reflux. After cooling, 100 ml of methylene chloride are added, and the reaction mixture is washed with 1N HCl, aqueous soda solution and saturated sodium chloride solution. The organic phase is dried and filtered, and the filtrate is concentrated, affording 3.8 g (73.4% of theory) of a red liquid resin. For the purpose of characterisation, a sample is distilled in a bomb tube. The distillate is a pale yellow oil; η25 =310 mPas.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:34]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[C:42]([CH2:51]OS(C)(=O)=O)[C:43](=[O:50])[N:44]([CH2:46][CH:47]([CH3:49])[CH3:48])[N:45]=2)=[CH:36][CH:35]=1.CN1CCNCC1>>[C:34]1([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[C:42]([CH2:51][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)[C:43](=[O:50])[N:44]([CH2:46][CH:47]([CH3:49])[CH3:48])[N:45]=2)=[CH:36][CH:35]=1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CC(C)Cn1nc(-c2ccc(-c3ccccc3)cc2)cc(COS(C)(=O)=O)c1=O
Agent: CN1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(-c3ccccc3)cc2)cc(CN2CCN(C)CC2)c1=O
Yield: 68.2 %

Procedure:
Following the procedure of Example 1 (10), 6-(4-biphenylyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 68.2%).
Reaction SMILES: O[N:2]=[C:3]([C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.[C:21](O)(=[O:23])[CH3:22]>C(OC(=O)C)(=O)C.[Zn]>[C:21]([NH:2][CH:3]([C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:23])[CH3:22]
Reactant: CCOC(=O)C(=NO)C(=O)CCc1cccc(C)c1
Reactant: CC(=O)O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(NC(C)=O)C(=O)CCc1cccc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Zinc dust (10 micron, 150 g) was added portionwise to a stirred solution of the product from step (i) (88 g) in acetic acid (400 ml) and acetic anhydride (125 ml) keeping the internal temperature below 40° C. The solution was stirred at room temperature for a further 1 hour before adding water (500 ml) dropwise at such a rate so as to keep the internal temperature below 40° C. The mixture was stirred at room temperature for a further 16 h then filtered and the mother liquor extracted with chloroform. The organic extracts were further washed with brine and water, collected dried over magnesium sulphate and solvent removed under reduced pressure to give the subtitle product.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10](=[O:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13](O)[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CN1CCOCC1.O>[CH2:13]([O:12][C:10]1[NH:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1)[CH3:14]
Reactant: O=C1CC(c2ccccc2)=NN1
Reactant: CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCOCC1
Solvent: O
Product: CCOc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 3-phenyl-1H-pyrazol-5(4H)-one (1.0 g, 6.24 mmol), ethanol (0.288 g, 6.24 mmol) and triphenylphosphine (1.638 g, 6.24 mmol) in N-methylmorpholine (7 mL) was added diethylazo dicarboxylate (0.988 mL, 6.24 mmol) dropwise at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was poured into H2O and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.89 g). LCMS m/z=189.19 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (t, J=4.2 Hz, 3H), 4.32 (q, J=4.2 Hz, 2H), 6.45 (s, 1H), 7.41-7.94 (m, 5H), 11.3 (s, 1H).
Reaction SMILES: [Br:1][Si](C)(C)C.CS(C)=O.[N:10]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11]1.O>CC#N.CCOC(C)=O>[Br:1][C:12]1[CH:13]=[CH:14][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:11]=1
Reactant: c1ccc(-n2cccc2)nc1
Reactant: C[Si](C)(C)Br
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Brc1ccn(-c2ccccn2)c1
Reaction time: 0.17 h

Procedure:
Bromotrimethylsilane (10.9 mL, 84 mmol) was added to DMSO (5.7 mL, 84 mmol) in MeCN (200 mL) at 0° C. After stirring for 10 min, 2-(1H-pyrrol-1-yl)pyridine (10 g, 70 mmol) in MeCN (50 mL) was added. The reaction mixture was stirred at 0° C. and allowed to reach rt over 3 h. H2O (150 mL) and EtOAc (150 mL) were added and the reaction mixture was shaken, the EtOAc layer was separated and the aqueous layer shaken with EtOAc (3×150 mL). The combine organic layers were dried over Na2SO4 and concentrated to a brown oil. LCMS indicated good conversion to 2-(3-bromo-1H-pyrrol-1-yl)pyridine and this was used without further purification. (MS (ESI) 224 (M+H)+.
Reaction SMILES: [Br:1][CH:2]([CH3:12])[CH:3]([P:8]([Cl:11])([Cl:10])=O)[O:4][C:5](=[O:7])[CH3:6].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>>[Br:1][CH:2]([CH3:12])[CH:3]([P:8]([Cl:11])([Cl:10])=[S:14])[O:4][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)OC(C(C)Br)P(=O)(Cl)Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: CC(=O)OC(C(C)Br)P(=S)(Cl)Cl

Procedure:
One and one-quarter grams of (2-bromo-1-acetoxypropyl)phosphonic dichloride is heated with 0.55 g. of finely pulverized P2S5 under nitrogen at 130°C. for three hours. The reaction mixture is fractionally distilled to give threo (2-bromo-1-acetoxypropyl)phosphonothioic dichloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=1>>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:38](=[O:39])[C:35]3[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:37][N:36]=3)[CH:3]=[CH:4][C:5]=2[F:29])[N:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: COc1ccc(C(=O)O)nc1
Product: COc1ccc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C(F)(F)F)[C@H]3CSC(N)=N4)c2)nc1

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-methoxypyridine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.88 (dd, J=13.8, 3.7 Hz, 1H), 3.23 (dd, J=13.8, 2.4 Hz, 1H), 3.46 (d, J=7.3 Hz, 1H), 3.89-4.02 (m, 4H), 4.54-5.00 (m, 4H), 7.11 (dd, J=11.9, 8.8 Hz, 1H), 7.36 (dd, J=8.8, 2.8 Hz, 1H), 7.61 (dd, J=7.1, 2.8 Hz, 1H), 7.97 (dt, J=8.5, 3.6 Hz, 1H), 8.23-8.30 (m, 2H), 9.86 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH:14]=O)=[O:4].CC(O)=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH2:14][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2[nH]nc(C=O)c2c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]nc(CN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 3-formyl-1H-indazole-5-carboxylic acid methyl ester (600 mg, 2.94 mmol) in DCM was added HOAc (0.25 mL, 4.41 mmol) followed by morpholine (0.31 mL, 3.53 mmol) and NaHB(OAc)3 (809.6 mg, 3.62 mmol) at rt. The reaction was stirred at rt overnight, and was quenched with brine. The reaction mixture was extracted with EtOAc, washed with brine, dried, and concentrated in vacuo. Purification by flash column afforded 3-(4-morpholinylmethyl)-1H-indazole-5-carboxylic acid methyl ester (800 mg, 95.7%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([CH3:13])[C:8]=1[OH:12])[O:5][C:4](=[O:14])[CH:3]=[C:2]2[CH3:1])([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(=O)oc2c(C)c(O)ccc12
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)oc2c(C)c(O)c([N+](=O)[O-])cc12
Reaction time: 3 h
Yield: 81 %

Procedure:
4,8-Dimethyl-7-hydroxycoumarin (7.50 g, 39.4 mmoles) was dissolved in 75 ml concentrated sulfuric acid at room temperature and chilled to −20° C. before the addition of chilled nitrating mixture (3 ml concentrated nitric acid added to 9 ml concentrated sulfuric acid). Stirring was continued for three hours at −20° C. with the mixture allowed to warm before pouring into ice. Bright yellow crystals were filtered, washed with water and dried to recover 7.50 g (81% yield). The product was recrystallized from ethanol to give yellow green crystals: mp 229.5-231.5° C.; 1H-nmr (dimethyl sulfoxide-d6):δ 2.29 (s, 3H), 2.41 (s, 3H), 6.37 (s, 1H), 8.19 (s, 1H), 11.30 (s, 1H); 13C-nmr (dimethyl sulfoxide-d6):δ 8.8, 18.0, 112.4, 112.9, 115.1, 119.9, 132.8, 152.9, 154.2, 155.1, 159.0; ms: (EI) m/z (relative intensity) 236 (M+, 23), 235 (M+, base) 207 (84), 77 (30).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:11][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(NC(=O)c2ccnc(Br)c2)c1

Procedure:
In a manner similar to that described in Preparation 17, 2-bromoisonicotinic acid and m-toluidine were converted to the title compound
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21](C#N)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:26](=[O:29])([O-])[O-:27].[Na+].[Na+]>S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:26]([OH:27])=[O:29])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(C#N)cn34)ccnc2c1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(OCc3nnc4ccc(C(=O)O)cn34)ccnc2c1
Temperature: 100 °C
Yield: 89 %

Procedure:
3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile (0.050 g, 0.15 mmol) was dissolved in concentrated sulfuric acid (0.375 mL) and water (0.125 mL). The reaction mixture was heated at 100° C. for 3.5 hours then slowly poured in to ice. The mixture was adjusted to approx. pH 7 with saturated aqueous sodium carbonate. A precipitate formed which was collected on a glass frit, washing with water. The solid was dried under high vacuum to afford 3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.047 g, 89% yield) as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8]>C(OCC)(=O)C.[Rh]>[CH3:1][CH:2]1[CH2:6][CH2:5][O:4][CH:3]1[C:7]([OH:9])=[O:8]
Reactant: Cc1ccoc1C(=O)O
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CC1CCOC1C(=O)O
Reaction time: 6.5 h

Procedure:
3-Methyl-2-furoic acid (5 g) in ethyl acetate (100 ml) and 5% rhodium on charcoal catalyst (0.5 g) were hydrogenated at ambient temperature and the atmosphere for 6-7 h. The catalyst was filtered off and replaced with a further quantity (1 g) of catalyst. The reaction mixture was hydrogenated for a further 7 h. This procedure was repeated again until no more hydrogen was absorbed. After filtration through kieselguhr and removal of solvent under reduced pressure, the title compound was obtained as a colourless oil (5.096 g, quant.); νmax (CH2Cl2) 3674, 3377(br), 1770 and 1722 cm-1 ; δH (CHC13) 1.08 (3 H, d, J 7.1 Hz), 1.72 (1 H, m), 2.16 (1 H, m), 2.68 (1 H, m), 3.94 (1 H, m), 4.18 (1 H, m), 4.47 (1 H, d, J 7.5 Hz) and 9.42 (1 H, v. br s, exch). [Mass spectrum: +ve ion (ammonia) MNH4+ (148)].
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([OH:12])[CH2:7][O:8][CH2:9][CH2:10]O.[OH-].[K+].C1(C=CC(O)=CC=1)O>S(=O)(=O)(O)O>[C:1]([O:5][CH2:10][CH2:9][O:8][CH2:7][CH2:6][OH:12])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)O
Reactant: OCCOCCO
Agent: O=S(=O)(O)O
Agent: Oc1ccc(O)cc1
Agent: [K+]
Product: C=CC(=O)OCCOCCO

Procedure:
Using 0.3 g (0.003 mole) of sulfuric acid as a catalyst, 72 g (1 mole) of acrylic acid was reacted with 106 g (1 mole) of diethylene glycol. The reaction mixture was neutralized with 0.34 g (0.006 mole) of potassium hydroxide, and 0.16 g (0.1 mass %) of hydroquinon was added as a stabilizer. Thus, diethylene glycol monoacrylate (A1-5) was obtained.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]([F:15])([F:14])[F:13])[CH:9]=2)[N:4]([CH3:16])[N:3]=1.C([Mg]Cl)(C)C.[CH2:22]([Sn:26]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])Cl)[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH3:16][N:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=2)[C:2]([Sn:26]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:22][CH2:23][CH2:24][CH3:25])=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1nc(I)c2cc(OC(F)(F)F)ccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(OC(F)(F)F)cc12
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
3-Iodo-1-methyl-5-(trifluoromethoxy)-1H-indazole (0.141 g, 412 μmol) was dissolved in THF (3.00 mL). The colorless solution was cooled to −16° C. (NaCl/ice bath), then isopropylmagnesium chloride 2M in THF (231 μL, 462 μmol) was added dropwise at −16° C. The reaction mixture was stirred at −16° C. for 20 min. Tributylchlorostannane (154 mg, 129 μL, 474 μmol) was added slowly. The reaction mixture was warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with dichloromethane (3×30 mL), the organics dried over MgSO4 and concentrated to a yellow oil. The residue was dried under high vacuum and taken into the next step without further purification.
Reaction SMILES: [C:1]1([C:7]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[NH:19][C:18]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[N:17][CH:16]=3)=[CH:11][N:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([CH:7]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[NH:19][C:18]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[N:17][CH:16]=3)=[CH:11][N:10]=2)[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccccc1)c1ncc(-c2cnc(-c3cccnc3)[nH]2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccccc1)c1ncc(-c2cnc(-c3cccnc3)[nH]2)cn1
Reaction time: 1 h

Procedure:
To a solution consisting of phenyl(5-(2-(pyridin-3-yl)-1H-imidazol-5-yl)pyrimidin-2-yl)methanone (Example 67) dissolved in methanol is added sodium borohydride (1 molar equivalent) at 0° C. The mixture is allowed to reach room temperature and is stirred one hour. The mixture is partitioned between ethyl acetate and water and the organics washed with brine, dried (Na2SO4), filtered and concentrated to afford the title compound.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][O:10][SiH:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CC([O-])(C)C.[K+]>>[C:1]1([C:7]2[Si:11]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:13])[CH3:14])[O:10][CH2:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)[SiH](OCC#CC1=CCCCC1)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)[Si]1(C(C)C)OCC=C1C1=CCCCC1

Procedure:
Using (3-cyclohexenylprop-2-ynyloxy)diisopropylsilane (0.715 g, 2.854 mmol) and KOtBu (0.037 g, 0.330 mmol) produced a crude product as a colorless, clear liquid which upon flash chromatography yielded the title compound as clear colorless liquid; Rf 0.45 (hexanes/Et2O, 15:2). The isolated compound was found to have an impurity of about ˜20% with a close Rf value, hence the compound was further purified by using a chromatotron (2.0 mm silica gel) (0.537 g, 2.144 mmol, 75.1%). 1H NMR (300 MHz, CDCl3) δ 6.56 (s, 1H, H-4), 5.57 (s, 1H, H-9), 4.61 (s, 1H, H-5), 2.17-2.26 (m, 2H, H-13), 2.03-2.16 (m, 2H, H-10), 1.64-1.75 (m, 2H, H-12), 1.52-1.64 (m, 2H, H-11), 1.06-1.20 (m, 2H, H-6), 1.04 (d, J=6.6 Hz, 6H, H-7), 0.98 (d, J=6.8 Hz, 6H, H-7); 13C NMR (300 MHz, CDCl3) δ 140.3 (C-3), 138.0 (C-4), 135.7 (C-8), 128.9 (C-9), 77.8 (C-5), 26.2 (C-13), 26.0 (C-10), 22.8 (C-12), 22.4 (C-11), 17.4 (C-7), 17.1 (C-7), 13.4 (C-6); HRMS calcd for C15H27OSi (M+H)+ 251.1831. found 251.1828.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14](O)=[O:15])[CH:12]=2)[C:7]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[CH:6]1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:35][C@@H:36]([CH2:50][C:51]1[CH:56]=[C:55]([F:57])[CH:54]=[C:53]([F:58])[CH:52]=1)[C@H:37]([OH:49])[CH2:38][NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH3:48])[CH:42]=1>ClCCl>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:35][C@@H:36]([CH2:50][C:51]3[CH:52]=[C:53]([F:58])[CH:54]=[C:55]([F:57])[CH:56]=3)[C@H:37]([OH:49])[CH2:38][NH:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][CH3:48])[CH:42]=3)=[O:15])[CH:12]=2)[C:7]([C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(C(=O)C(F)(F)F)c2ccc(C(=O)O)cc21
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCCCn1cc(C(=O)C(F)(F)F)c2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
1-Butyl-3-(trifluoroacetyl)-1H-indole-6-carboxylic acid (0.141 g) was dissolved in dichloromethane (10 mL). 1,1′-Carbonyldiimidazole (0.080 g) was added and the mixture was stirred at room temperature for 2 h. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.166 g) in dichloromethane was added and the mixture was allowed to stir overnight at room temperature. The mixture was then partitioned between dichloromethane and water, dried over sodium sulfate, filtered, and concentrated. Chromatography on silica gel using methanol/ethyl acetate/heptane/dichloromethane (3/10/10/77 to 6/10/10/74) gave 1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-(trifluoroacetyl)-1H-indole-6-carboxamide (0.155 g). MS (ESI+) for C34H36F5N3O3+H1 m/z 630.28 (M+H)+.