Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][CH:9]([CH3:13])[C:8]2=[O:14])=[CH:4][CH:3]=1.CI.[C:19](O)(CC)(C)C.[H-].[Na+]>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][C:9]([CH3:19])([CH3:13])[C:8]2=[O:14])=[CH:15][CH:16]=1
Reactant: CC1CCCC(=Cc2ccc(Cl)cc2)C1=O
Reactant: CCC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CCCC(=Cc2ccc(Cl)cc2)C1=O
Temperature: 45 °C

Procedure:
2-(4-Chlorobenzylidene)-6-methylcyclohexanone (7.0 g), prepared above, and then methyl iodide (5.1 g) are added successively to a reaction medium prepared from toluene (25 cc), tert-amyl alcohol (3.6 cc) and sodium hydride (1.35 g of 60% strength dispersion in oil) and heated to 45° C. The mixture is brought to reflux (1 h), poured into water and extracted with ethyl acetate. After drying and concentration, the residue is recrystallized in methanol to give 2-(4-chlorobenzylidene)-6,6-dimethylcyclohexanone (4.7 g), m.p. 92°.
Reaction SMILES: CN(C)C=O.[CH3:6][NH:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]([C:26]23[O:33][CH2:32][C:29]([CH3:34])([CH2:30][O:31]2)[CH2:28][O:27]3)[CH:11]1[CH3:35])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:43][C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[CH3:51]>C(OCC)(=O)C>[CH3:6][NH:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:43][C:44]3[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=3[CH3:51])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]([C:26]23[O:33][CH2:32][C:29]([CH3:34])([CH2:28][O:27]2)[CH2:30][O:31]3)[CH:11]1[CH3:35])=[O:9]
Reactant: Cc1ccc(F)cc1CBr
Reactant: CNC(=O)N1CCN(S(=O)(=O)c2ccc(O)cc2)C(C23OCC(C)(CO2)CO3)C1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)N1CCN(S(=O)(=O)c2ccc(OCc3cc(F)ccc3C)cc2)C(C23OCC(C)(CO2)CO3)C1C
Temperature: 45 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
To a N,N-dimethylformamide (1.5 ml) solution of 4-(4-Hydroxy-benzenesulfonyl)-2-methyl-3-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-piperazine-1-carboxylic acid methylamide (compound of formula XLV, 0.31 g, 0.7 mmol) was added cesium carbonate (0.45 g) and 2-bromomethyl-4-fluoro-1-methyl-benzene (0.214 g, 1.05 mmol). The reaction mixture was stirred at about 45° C. for about 16 hours and then was allowed to cool and was diluted with ethyl acetate and washed with water. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 0.377 g of a compound of formula XLIV.
Reaction SMILES: C(O)[C@H]1O[C@H]([O:8][C@:9]2(CO)[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11](O)[C@@H:10]2O)[C@H](O)[C@@H](O)[C@@H]1O.N[C:25](N)=O.[Cl-].[K+].[O-]S([O-])(=O)=O.[Mg+2].OP([O-])(O)=O.[K+].C(O)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O>[O-]S([O-])(=O)=O.[Cu+2].[O-]S([O-])(=O)=O.[Mn+2].O.[O-]S([O-])(=O)=O.[Zn+2].O>[CH3:25][C:10]([C:9]([O:13][CH2:12][CH2:14][OH:15])=[O:8])=[CH2:11]
Reactant: NC(N)=O
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: [Cu+2]
Agent: [Mn+2]
Agent: O=P([O-])(O)O
Solvent: O
Product: C=C(C)C(=O)OCCO

Procedure:
Aspergillus oryzae strain SE01-28 described in Example 9 was transformed with pSE38 to create new transformants designated Aspergillus oryzae SE27 according to the method described in Example 8 with the exceptions that Basta resistance was used for selection and 2-8 μg of NdeI digested pSE38 was added per transformation directly from the reaction so that ~5 U of enzyme was included in the transformation mixture. Media for Basta selection contained 20 ml of COVE salts, 1 M sucrose, 25 g/L Noble agar, 10 mM Urea, and either 5 mg/ml Basta (Hoechst Schering, Rodovre, Denmark) for transformation or 10 mg/ml Basta for maintaining transformants. The COVE salts were composed of 26 g of KCl, 26 g of MgSO4 -7H2O, 76 g of KH2PO4, and 50 ml of COVE trace elements per liter of deionized water. The COVE trace elements were composed of 0.04 g of Na2B4O7 -10H2O, 0.4 g of CuSO4 -5H2O, 1.2 g of FeSO4 -7H2O, 0.7 g of MnSO4 -H2O, 0.8 g of Na2MoO2 -H2O, 10 g of ZnSO4 -7H2O per liter of deionized water. Maltose was added to a final concentration of 2.5%, when indicated. Basta selection overlay medium was the same as above except that Basta was added prior to use.
Reaction SMILES: [N:1]1([CH2:7][CH:8]([OH:11])[CH2:9][OH:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:28]([O-:30])=[O:29]>C(#N)C>[N+:28]([C:16]1[CH:17]=[C:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[CH:19]=[CH:20][C:15]=1[O:11][CH:8]([CH2:9][O:10][C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]([F:26])([F:27])[F:25])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:28]([O-:30])=[O:29])[CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: OCC(O)CN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1OCC(CN1CCOCC1)Oc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Using the same procedure as for Example 54, a mixture of 3-morpholin-4-yl-propane-1,2-diol (40 mg, 0.25 mmol), sodium hydride (60%, 30 mg) and 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (174 mg, 0.6 mmol) in acetonitrile (1 mL) was heated to reflux, worked-up and purified on silica gel to give the title compound. 1H NMR (360 MHz, DMSO-d6) δ 8.59 (d, J=2.3 Hz, 2H), 8.35 (dd, J=2.3 & 9.2 Hz, 1H), 8.30 (dd, J=2.3 & 9.2 Hz, 1H), 7.97 (d, J=9.2 Hz, 1H), 7.79 (d, J=9.2 Hz, 1H), 5.49 (m, 1H), 4.79 (m, 1H), 4.66 (m, 1H), 3.41 (m, 4H), 2.74 (d, J=6.1 Hz, 2H), 2.4-2.5 (m, 4H). MS+ve APCI 668 [M+1].
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[N:20][N:19]=[CH:18]2)=[CH:13][CH:12]=1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)(=O)C>[N:19]1[N:20]=[CH:21][N:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][OH:8])=[CH:16][CH:15]=2)[CH:18]=1
Reactant: c1ccc(COCCc2ccc(-n3cnnc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: OCCc1ccc(-n2cnnc2)cc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a stirred solution of 4-[4-(2-benzyloxyethyl)phenyl]-4H-[1,2,4]triazole (0.237 g in 20 mL methanol) was added 183 mg of 10% palladium hydroxide on carbon catalyst followed by 0.20 mL acetic acid. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 11 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride:methanol:ammonium hydroxide, 90:7:1) gave the title compound (0.147 g).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:21])[NH:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16](=O)[CH3:17])([CH3:10])([CH3:9])[CH3:8].[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23].Cl>O1CCCC1>[CH2:26]([O:25][C:22](=[O:24])/[CH:23]=[C:16](\[CH3:17])/[CH2:15][C:14]([NH:13][C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:21])([CH3:19])[CH3:20])[CH3:27]
Reactant: CC(=O)CC(C)(C)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Triethyl phosphonoacetate (4.7 g; 20.9 mmol) was dissolved in tetrahydrofuran (36 ml). Potassium tert-butoxide (2.3 g; 20.9 mmol) was added and the reaction mixture was stirred for 40 min at room temperature. (1,1-Dimethyl-3-oxobutyl)carbamic acid tert-butyl ester (2.5 g; 11.6 mmol) was dissolved in tetrahydrofuran (15 ml) and added dropwise to the reaction mixture which was heated to reflux for 12 h. Ethyl acetate (100 ml) and hydrochloric acid (1 N; 100 ml) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with an aqueous solution of sodium hydrogen carbonate (saturated; 100 ml), dried (magnesium sulfate) and evaporated in vacuo. The residue was purified by flash chromatography on silica (120 g) using ethyl acetate/heptane (1:2) as eluent to afford 2.0 g of (2E)-5-tert-butoxycarbonylamino-3,5-dimethylhex-2-enoic acid ethyl ester.
Reaction SMILES: [CH:1]1([CH2:4][C@H:5]([C@@H:28](OS(N2C=CN=C2)=O)[CH2:29][CH2:30][CH2:31][CH3:32])[C:6]([NH:8][C@H:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[N:11]([CH3:26])[C:10]2=[O:27])=[O:7])[CH2:3][CH2:2]1.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[O:7]=[C:6]([NH:8][C@H:9]1[N:15]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]([CH3:26])[C:10]1=[O:27])[C@@H:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCC[C@H](OS(=O)n1ccnc1)[C@@H](CC1CC1)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCCC[C@H](CC1CC1)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Yield: 84.7 %

Procedure:
A solution of 4 (190 mg, 0.350 mmol), from step 2, in 10 mL of dry and degassed toluene was heated to reflux. A solution of tri-n-butyltin hydride (210 mg, 0.700 mmol) in 1 mL of toluene was added dropwise over 30 min. After an additional 5 h of reflux, the reaction was cooled, concentrated under reduced pressure. The crude mixture was purified by flash chromatography (elution with hexanes initially to remove tin-containing materials, then with 40% ethyl acetate-hexane) to afford 128 mg (85%) of compound 5 as a colorless gel. 1H NMR (300 MHz, CDCl3) δ 7.21-7.66 (10H, m), 5.60 (1H, d, J=8.4 Hz), 3.47 (3H, s), 2.30 (1H, m), 1.21-1.84 (10H, m), 0.91 (3H, t, J=6.2 Hz), 0.76 (1H, m), 0.46 (2H, m), 0.06 (2H, m); MS (ESI): 432 (M+H), 455 (M+Na), 430 (M−H).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:16]C(=O)OC(C)(C)C)[C:9]([NH:11][CH2:12][CH2:13][C:14]#[N:15])=O)=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Si]([N:67]=[N+:68]=[N-:69])(C)(C)C>C1COCC1>[NH2:16][C@H:8]([C:9]1[N:11]([CH2:12][CH2:13][C:14]#[N:15])[N:69]=[N:68][N:67]=1)[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:2][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCCn1nnnc1[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of (S)-tert-butyl 3-(biphenyl-4-yl)-1-(2-cyanoethylamino)-1-oxopropan-2-ylcarbamate (563 mg, 1.431 mmol) and triphenylphosphine (450 mg, 1.717 mmol) in THF (10 mL) were added DIAD (0.334 mL, 1.717 mmol) and TMSN3 (0.228 mL, 1.717 mmol) at room temperature. After 2 hours, additional triphenylphosphine (180 mg, 0.687 mmol), DIAD (0.134 mL, 0.687 mmol) and TMSN3 (0.0912 mL, 0.687 mmol) were added. After being stirred overnight, additional triphenylphosphine (180 mg, 0.687 mmol), DIAD (0.134 mL, 0.687 mmol) and TMSN3 (0.0912 mL, 0.687 mmol) were added. After being additional 3 hours, the reaction mixture was concentrated and purified by silica gel flash column chromatography (eluent; EtOAc/heptane). The obtained product was treated with 4M HCl in dioxane (10 mL) at room temperature. After being stirred for 1 hour, the reaction mixture was concentrated. The residue was diluted with EtOAc, washed with saturated NaHCO3aq and brine. The organic layer was dried over Na2SO4, concentrated and purified by silica gel flash column chromatography (eluent; MeOH/DCM) to give (S)-3-(5-(1-amino-2-(biphenyl-4-yl)ethyl)-1H-tetrazol-1-yl)propanenitrile (334 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.83 (dt, J=6.82, 16.9 Hz, 1H), 2.96 (dt, J=6.82, 13.89 Hz, 1H), 3.21 (dd, J=8.08, 13.64 Hz, 1H), 3.42 (dd, J=6.06, 13.64 Hz, 1H), 4.47-4.59 (m, 2H), 4.60-4.68 (m, 1H), 7.21 (d, J=8.08 Hz, 2H), 7.33-7.39 (m, 1H), 7.42-7.48 (bt, 2H), 7.54-7.60 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]2[CH2:7][CH2:8][C:9]3[CH:15]=[C:14](CC(C(OCC)=O)C(OCC)=O)[CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2CCC3C=CC=[C:41]([C:45]([C:50]([O:52][CH2:53][CH3:54])=[O:51])(C)C([O-])=O)C=3SC=2C=1)#N>>[C:1]([C:3]1[CH:29]=[CH:28][C:6]2[CH2:7][CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[C:12]([CH2:41][CH2:45][C:50]([O:52][CH2:53][CH3:54])=[O:51])[C:10]=3[S:11][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(C)(C(=O)[O-])c1cccc2c1Sc1cc(C#N)ccc1CC2
Reactant: CCOC(=O)C(Cc1ccc2c(c1)CCc1ccc(C#N)cc1S2)C(=O)OCC
Product: CCOC(=O)CCc1cccc2c1Sc1cc(C#N)ccc1CC2
Yield: 97 %

Procedure:
Substituting ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]thiepin-2-yl)-2-ethoxycarbonylpropanoate in the foregoing example with an equivalent amount of ethyl 3-(7-cyano-10,11-dihydrodibenzo[b,f]-thiepin-4-yl-2-ethoxycarbonylpropanoate provided the title compound in 97% yield. The compound was purified by short-path distillation at an oven temperature of 190°/0.05 Torr and then has m.p. 61°-62° C. Analysis for: C20H19NO2S Requires: C 71.19, H 5.68, N 4.15, S 9.50; Found C 71.13, H 5.80, N 4.09, S 9.42.
Reaction SMILES: [OH:1][N:2]1[C:11]2[C:6](=[C:7]3[S:14][C:13](=[O:15])[NH:12][C:8]3=[CH:9][CH:10]=2)[C:5](=[O:16])[C:4]([C:17]([OH:19])=[O:18])=[CH:3]1.[OH-].[K+].O.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[CH2:23]([O:1][N:2]1[C:11]2[C:6](=[C:7]3[S:14][C:13](=[O:15])[N:12]([CH2:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:8]3=[CH:9][CH:10]=2)[C:5](=[O:16])[C:4]([C:17]([OH:19])=[O:18])=[CH:3]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1cn(O)c2ccc3[nH]c(=O)sc3c2c1=O
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(OCc2ccccc2)c2ccc3c(sc(=O)n3Cc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 44 h

Procedure:
To a mixture of 1.0 g of 2,3,6,9-tetrahydro-6-hydroxy-2,9-dioxothiazolo[5,4-f]quinoline-8-carboxylic acid, 0.96 g of an 85% -- potassium hydroxide aqueous solution, 20 ml of water and 7 ml of methanol was added dropwise 2.77 g of benzyl bromide and the mixture was stirred for 44 hours at room temperature.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH3:19])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:20]([O-])=[O:21].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:20]=[O:21])[C:5]([N:7]([CH3:19])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O=CO
Product: CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 45.6 %

Procedure:
1.2 g of 1-(2-chloroethyl)-3-methyl-3-D-glucopyranosylurea are dissolved in 10 ml of formic acid, and 0.56 g of sodium nitrite is added thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for 1.5 hours. After the reaction, the mixture is freeze-dried. The residue thus obtained is purified by silica gel chromatography(Solvent: chloroform-ethyl acetate-methanol(2:1:1)). 0.6 g of 1-(2-chloroethyl)-1-nitroso-3-methyl-3-D-glucopyranosylurea is thereby obtained as a pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)=[O:7].C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:42]([NH:44][CH2:45][CH3:46])[CH3:43]>C(Cl)Cl>[CH2:42]([N:44]([CH2:45][CH3:46])[C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:6](=[O:7])[C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:16][CH:15]=1)[CH3:43]
Reactant: COc1cccc(C(=O)c2ccc(C(=O)O)cc2)c1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(=O)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of 0.23 grams of acid (3.1b), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.2 equivalents with respect to the acid) and 1-hydroxy benzotriazol hydrate (1.2 equivalents) in anhydrous CH2Cl2 (2 ml) is stirred at room temperature for 30 minutes. A solution of diethylamine (1.5 equivalents) in anhydrous CH2Cl2 (8 ml) is then dropwise added. The obtained mixture is stirred at room temperature for 14 hours and washed in a first step with saturated aqueous sodium bicarbonate and in a second step with water. The organic phase is dehydrated with sodium sulphate, filtered and evaporated under vacuum. The residue that is recovered is purified by flash chromatography (ligroin/ethyl acetate 1/1 v/v). N,N-diethyl-4-(3′-methoxybenzoyl)benzamide (3.1c) is obtained. Yield: 98%. IR (nujol) (λ=cm−1) 1690 (C═O); 1H-NMR (CDCl3) δ 1.00-1.38 (m, 6H); 3.20-3.38 (m, 2H); 3.50-3.70 (m, 2H); 3.86 (s, 3H); 7.10-7.40 (m, 4H); 7.48 (d, 2H, J=8.4 Hz); 7.84 (d, 2H, J=8.4 Hz). Anal. calc. for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.11; H, 6.78; N, 4.49.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[Li]CCCC.CN([CH:21]=[O:22])C.O>C1COCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([CH:21]=[O:22])[CH:3]=[CH:4][C:5]=2[O:9][CH2:8]1
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COc2ccc(C=O)cc21
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 106.6 %

Procedure:
To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-benzofuran (example 1f) (15.90 g, 70.01 mmol) in dry THF (100 mL) at −78° C., under argon, was added dropwise n-BuLi (1.6 M in hexane, 105 mmol, 42 mL). The mixture was stirred for 5 minutes then DMF (16.3 mL, 210 mmol) was added and the mixture was quickly warmed up to −50° C. and then to 0° C. for 3 hrs. Water was added slowly and the solution extracted with ethyl acetate. The organic layer was further washed with water, brine, dried (MgSO4), filtered and evaporated to give 13.15 g of 3,3-dimethyl-2,3-dihydro-benzofuran-5-carbaldehyde use as this in the next step. 1H NMR (300 MHz; CDCl3): 1.38 (s, 6H), 4.36 (s, 2H), 6.89 (d, J=7.8 Hz, 1H), 7.68 (m, 2H), 9.85 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH:19]4[CH2:21][CH2:20]4)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[N:6][CH:7]=1.[CH3:22][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]#[CH:25].C(N(CC)CC)C.CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[CH:19]1([CH2:18][O:17][C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:5]4[N:6]=[CH:7][C:2]([C:25]#[C:24][C@@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:22])=[CH:3][CH:4]=4)[O:9][C:10]=3[CH:16]=2)[CH2:21][CH2:20]1
Reactant: C#C[C@H](C)NC(=O)OC(C)(C)C
Reactant: Brc1ccc(-c2nc3ccc(OCC4CC4)cc3o2)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H](C#Cc1ccc(-c2nc3ccc(OCC4CC4)cc3o2)nc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
Under an argon atmosphere, a mixture of 2-(5-bromopyridin-2-yl)-6-(cyclopropylmethoxy)-1,3-benzoxazole (200 mg), tert-butyl [(1S)-1-methylprop-2-yn-1-yl]carbamate (196 mg), dichlorobis(triphenylphosphine)palladium(II) (20.3 mg), copper(I) iodide (11.0 mg), triethylamine (0.081 mL) and DMF (5 mL) was stirred at 80° C. for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow powder (150 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:29]=[CH:28][C:15]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23](=[O:27])[C:24](O)=[O:25])[CH2:19][CH2:18]2)=[CH:14][CH:13]=1>C(OCC)C>[F:11][C:12]1[CH:29]=[CH:28][C:15]([CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:27])[C:24]([NH:1][C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[CH:4][CH:3]=3)=[O:25])[CH2:21][CH2:22]2)=[CH:14][CH:13]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc2cn[nH]c2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 6-aminoindazol (Aldrich) and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) according to the method described in Example 2. Melting Point: 162-164° C. (diethylether)
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:9]=2[CH:20]=1)[CH3:4].[O:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>C(N(CC)CC)C.ClCCCl>[ClH:1].[CH3:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([CH:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)[CH2:18][CH2:19]3)[C:9]=2[CH:20]=1)[CH3:2]
Reactant: CC(C)c1ccc2[nH]c(=O)n(C3CCNCC3)c2c1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)c1ccc2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2c1

Procedure:
6-(1-Methylethyl)-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride D35 (0.59 g) 1,2-dichloroethane (50 mL) and triethylamine (3 mL), tetrahydro-4H-pyran-4-one (0.9 g), sodium triacetoxyborohydride (1.9 g) was stirred at room temperature overnight. The mixture was poured into dilute ammonium chloride solution and extracted with dichloromethane. The organic phase was separated, washed with brine and dried with hydromatrix. The solvent was removed and the residue was chromatographed on silica gel eluted with dichloromethane/2M ammonia in methanol 0-10%. The resulting product was dissolved in a mixture of methanol and dichloromethane, treated with 1M hydrogen chloride in ether and the solvent was removed. Recrystallisation from methanol gave the title compound as a white solid from ether (0.486 g). Mass Spectrum MH+ 344
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(Cl)Cl>[CH2:44]([O:43][C:41]([O:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[CH:22][CH:23]=2)=[C:9](\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH2:10][CH3:11])=[CH:4][CH:3]=1)=[O:42])[CH3:45]
Reactant: CCOC(=O)Cl
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1ccc(/C(=C(/CC)c2ccccc2)c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of tert-butyl ester 12 (0.45 g, 1.06 mmol) in CH2Cl2 (20 mL) at 0° C. was added Et3N (0.32 mL, 0.23 g, 2.33 mmol) and ethyl chloroformate (0.115 mL, 0.126 g, 1.16 mmol) and the mixture stirred at ambient temperature for 1 h. The mixture was washed with ice-chilled 0.1 N hydrochloric acid and the organic layer dried (Na2SO4) and evaporated to provide compound 39 as an off-white solid (0.52 g, 99%); 1H NMR (DMSO-d6): δ 0.86 (t, J=7.1 Hz, 3H), 1.23 (t, J=7.5 Hz, 3H), 1.48 (s, 9H), 2.40 (q, J=7.5 Hz, 2H), 4.17 (q, J=7.1 Hz, 2H), 6.51 (d, J=16 Hz, 1H), 6.87 (d, J=9 Hz, 2H), 6.91 (d, J=9 Hz, 2H), 7.10-7.16 (m, 3H), 7.18-7.22 (m, 2H), 7.25 (d, J=8.1 Hz, 2H), 7.55 (d, J=16 Hz, 1H), 7.71 (d, J=8.1 Hz, 2H); MS, m/z 521 (M+Na)+.