Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH:12]([OH:17])[C:11]=3[C:10](=[O:18])[C:9]([C:19]([OH:21])=[O:20])=[CH:8]2)=[CH:4][CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:58][O:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CS(C)=O>[OH:17][CH:12]1[CH2:13][CH2:14][CH2:15][C:16]2[N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=4[O:59][CH3:58])=[CH:3][CH:4]=3)[CH:8]=[C:9]([C:19]([OH:21])=[O:20])[C:10](=[O:18])[C:11]1=2
Reactant: O=C(O)c1cn(Cc2ccc(Br)cc2)c2c(c1=O)C(O)CCC2
Reactant: COc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1-c1ccc(Cn2cc(C(=O)O)c(=O)c3c2CCCC3O)cc1
Temperature: 80 °C

Procedure:
A 2-dram screw-cap vial was charged with the above carboxylic acid (51 mg, 0.13 mmol), X-Phos (7.7 mg, 0.016 mmol), 2-methoxyphenyl boronic acid (32 mg, 0.21 mmol), and dimethyl sulfoxide (1 mL). The mixture was stirred vigorously and potassium carbonate (46 mg, 0.33 mmol) in 0.2 mL of water was added along with palladium (II) acetate (3.6 mg, 0.0053 mmol). The mixture was heated at 80° C. for 90 minutes, cooled to ambient temperature and filtered. The mixture was purified via preparative reverse phase HPLC to provide the titled compound: 1H-NMR (500 MHz, d6-DMSO) δ 8.93 (1H, s), 7.51 (2H, d, J=10.4 Hz), 7.35 (1H, t, J=7.4 Hz), 7.28 (1H, d, J=7.4 Hz), 7.17 (2H, d, J=8.9 Hz), 7.11 (1H, d, J=7.4 Hz), 7.02 (1H, t, J=7.4 Hz), 5.59 (1H, d, J=16.3 Hz), 5.52 (1H, d, J=16.3 Hz), 4.89 (1H, br s), 3.75 (3H, s), 2.83 (1H, m), 1.87 (1H, m), 1.79-1.73 (2H, m), 1.48 (1H, m) ppm; high resolution mass spectrum (ES+) m/z 406.1631 [(M+H)+; calculated for C24H24NO5: 406.1649].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([CH:15]([C:23]#[N:24])[CH2:16][CH2:17][C:18](OCC)=[O:19])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Ni].C(O)C>[O:19]=[C:18]1[NH:24][CH2:23][CH:15]([C:12]2[N:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: CCOC(=O)CCC(C#N)c1cnc(NC(=O)OC(C)(C)C)cn1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cnc(C2CCC(=O)NC2)cn1
Temperature: 56 °C

Procedure:
Under Argon, to ethyl 4-(5-(tert-butoxycarbonylamino)pyrazin-2-yl)-4-cyanobutanoate in ethanol solution (94 mg, 0.281 mmol/8 mL) was added Raney Nickel catalyst ethanol suspension (Nickel in ˜2 mL ethanol, the amount of Raney Nickel was not accurately measured), and the reaction mixture was stirred under H2 balloon after 3 times air atomasphere exchange heated with external oil bath at 56° C. for overnight with H2 balloon. The reaction mixture was cooled down to room temperature, and filtered through a pad of Celite, the filtrate was concentrated to afford tert-butyl 5-(6-oxopiperidin-3-yl)pyrazin-2-ylcarbamate in a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[N:18][C:19]=3[NH2:21])[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][NH:24]3)[N:13]=2)=[CH:8][CH:7]=1.[C:32]([CH2:34][C:35](O)=[O:36])#[N:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:35](=[O:36])[CH2:34][C:32]#[N:33])[N:13]=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:28]=[C:29]([F:31])[CH:30]=[C:2]([F:1])[CH:3]=4)=[CH:11][CH:10]=3)[C:20]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)cc(F)c3)cc1)nn2C[C@H]1CCCN1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
Into a 100 mL, round-bottom flask, was placed 3-[4-(3,5-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (185 mg, 0.44 mmol, 1.00 equiv), 2-cyanoacetic acid (30.7 mg, 0.36 mmol, 0.80 equiv), HATU (138 mg, 0.36 mmol, 0.80 equiv), triethylamine (91 mg, 0.90 mmol, 2.00 equiv), and N,N-dimethylformamide (50 mL). The resulting solution was stirred for 3 h at 25° C. and then extracted with ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 101 mg (47%) of 3-[(2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as a off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([Cl:19])=[C:16](Cl)[S:17][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>C1COCC1.CCCCCC>[CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([Cl:19])=[C:16]([C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH3:25])[S:17][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1sc2c(c1Cl)CCN(Cc1ccccc1)CC2
Reactant: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1sc2c(c1Cl)CCN(Cc1ccccc1)CC2
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
The product from step (g) (109 mg, 0.35 mmol) in anhydrous THF (5 ml) was cooled to −78° C. under a nitrogen atmosphere and treated with 1.6 M n-butyl lithium in hexane (0.25 ml). The reaction mixture was stirred at −78° C. for 5 minutes followed by the addition of trimethyl acetyl chloride (0.22 ml, 1.75 mmol). After 10 additional minutes at −78° C., the reaction mixture was allowed to warm to room temperature. The reaction was quenched with saturated NaHCO3 (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts were washed with brine (50 ml), dried (MgSO4), and solvent evaporated in vacuo to give the subtitled compound as an orange oil which was used in the next step without further purification. MS: ESI (positive): 362, 364 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C@H:8]1[C@@:25]2([CH3:26])[C:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:27])=[CH:11][C:10](=[O:28])[CH2:9]1.[Cl-].[NH4+]>CS(C)=O>[CH3:7][C@H:8]1[C@@:25]2([CH3:26])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:27])[CH2:11][C:10](=[O:28])[CH2:9]1
Reactant: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CC(=O)CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C

Procedure:
To a solution of potassium t-butoxide in dimethylsulfoxide at 25° C. under nitrogen is added 1β-methyl-4-androstene-3,17-dione in dimethylsulfoxide with stirring. After 15 minutes the mixture is poured onto cold aqueous ammonium chloride. The solid is rapidly filtered, washed well with water and dissolved in ether. The ether is washed with water, dried over sodium sulfate and removed at room temperature to yield 1β-methyl-5-androstene-3,17-dione.
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[C:21]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[CH3:28]>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=3[CH3:28])[CH2:30][CH2:31]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cccc(C)c2C)CC1
Yield: 72 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(2,3-xylyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[S:10][C:11]([NH:23]C(=O)OC(C)(C)C)=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[N:13]=1>C(Cl)Cl.O>[Br:8][C:9]1[S:10][C:11]([NH2:23])=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[N:13]=1
Reactant: COc1ccc(Cl)cc1-c1nc(Br)sc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1-c1nc(Br)sc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
TFA (4.0 mL) was added to a solution of tert-butyl 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-ylcarbamate (360 mg, 0.86 mmol) in DCM (10 mL) and water (3 drops). The reaction mixture was stirred for 1.5 hours at room temperature and then evaporated to dryness. The residue was taken up into DCM and washed with sodium hydrogen carbonate (sat.aq.), water and brine, and concentrated under vacuum to give 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine as an orange residue. LCMS (method 1) [M+H]+=321.3, RT=3.63 min. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.36 (d, 1H), 7.34-7.32 (m, 1H), 7.10 (d, 1H), 3.83 (s, 3H).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH2:25])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:25][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)=[CH:22][CH:21]=1
Reactant: C=Cc1ccc(OC)cc1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(/C=C/c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)cc1
Solvent: CN(C)C=O
Product: COc1ccc(C=Cc2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (from Example 71 above) (100 mg, 0.29 mmol) in DMF (3 mL) and TEA (2 mL) was added p-methoxy-styrene (79 mg, 0.58 mmol) (from Step A above), tri-o-tolylphosphine (107 mg, 0.35 mmol) (Aldrich) and Pd(OAc)2 (20 mg, 0.089 mmol) (Aldrich). The reaction mixture was stirred at 85° C. overnight in a pressure tube. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (Hex:EtOAc=5:1) to provide 1,3-dihydro-4-[(E)-2-(4-methoxyphenyl)-ethenyl]-(Z)-3-[(1H-pyrrol-2-yl)methlene]-2H-indol-2-one as a yellow solid. (Yield 72 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19](O)(=[O:21])[CH3:20].O>O1CCOCC1>[C:19]([NH:1][C:2]1[C:7]2[C:8](=[O:18])[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: Nc1cccc2c(=O)[nH]c3ccccc3c(=O)c12
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cccc2c(=O)[nH]c3ccccc3c(=O)c12

Procedure:
To 2.5 g 10-amino-5,6-dihydro-11H-dibenzo(b,e)azepine-6,11-dione in 50 ml dioxane are added 2 ml anhydrous acetic acid. This mixture is kept at reflux for 2 hours then brought almost to dryness under reduced pressure, and then poured into water, filtered and dried. Yield 2 g (ethanol): melting point 270°-2° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)C(Cl)=O)([O-:26])=[O:25]>C(Cl)(Cl)Cl>[CH3:12][O:11][C:9]1[C:8]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:1][C:34]2[CH:33]=[CH:29][CH:28]=[C:27]([N+:24]([O-:26])=[O:25])[CH:35]=2)[CH:10]=1
Reactant: COCCOc1cc(C(N)=O)c(N)cc1OC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COCCOc1cc(C(N)=O)c(Nc2cccc([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 2-amino-4-methoxy-5-(2-methoxyethoxyl)benzamide (1.78 g, 7.40 mmol) and pyridine (2.40 mL, 29.6 mmol) in CHCl3 (40 mL) was added 3-nitrobenzoyl chloride (1.44 g, 7.8 mmol). The mixture was stirred at RT for 2.5 h upon which the mixture was concentrated in vacuo to give the desired product, which was used directly in the next step without purification.
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:13][CH2:12][C:5]2([NH:9]C(=O)N[C:6]2=[O:11])[CH2:4][CH2:3]1.[OH-:15].[K+]>>[NH2:9][C:5]1([C:6]([OH:15])=[O:11])[CH2:12][CH2:13][C:2]([F:14])([F:1])[CH2:3][CH2:4]1
Reactant: [OH-]
Reactant: O=C1NC(=O)C2(CCC(F)(F)CC2)N1
Agent: [K+]
Product: NC1(C(=O)O)CCC(F)(F)CC1

Procedure:
Under nitrogen gas, 4.10 g of the compound of Example 2A were suspended in 100 ml of 30% strength aqueous potassium hydroxide solution, and the mixture was stirred at reflux overnight. The mixture was concentrated to about 25% of the volume and, at 0-10° C., adjusted to pH 5.5 using concentrated aqueous hydrogen chloride solution. The solution was concentrated and dried. The residue (4.30 g) was used directly for the esterification.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[C:8]2=[O:33])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[C:8]2=[O:33])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(CC)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C3CCCCC3)c2=O)cc1
Reaction time: 8 h
Yield: 69 %

Procedure:
Ethyl N-({1-cyclohexyl-3-[(4-ethylphenyl)methyl]-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl}carbonyl)glycinate (product b from example 43) was dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (195 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (br. s., 1 H), 10.15 (s, 1 H), 7.18-7.24 (m, 2 H), 7.13-7.18 (m, 2 H), 4.95 (s, 2 H), 4.64 (t, J=11.62 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 2.56 (q, J=7.58 Hz, 2 H), 2.20-2.31 (m, 2 H), 1.78 (d, J=12.13 Hz, 2 H), 1.61 (d, J=10.36 Hz, 3 H), 1.28 (q, J=12.72 Hz, 2 H), 1.06-1.17 (m, 4 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C@@H:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:11]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:39]([NH3+:43])[CH:40]([CH3:42])[CH3:41].C([BH3-])#N.[Na+]>CO>[CH2:39]([NH:43][CH2:11][C@@H:10]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:40]([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](C=O)OCc1ccccc1
Reactant: CC(C)C[NH3+]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)CNC[C@@H](OCc1ccccc1)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 0.75 h
Yield: 87 %

Procedure:
A solution of (S)-3-t-butoxycarbonylamino-(R)-2-benzyloxy-4-cyclohexylbutyraldehyde (600 mg.) and isobutylammonium p-toluenesulfonate (510 mg.) were stirred together in methanol for 30 minutes at 20° C. and then treated in one portion with sodium cyanoborohydride (105 mg.). After 45 minutes 28 mg. more sodium cyanoborohydride was added and 30 minutes later the mixture was filtered through Celite, concentrated, the residue dissolved in ethyl acetate which was washed twice with aqueous bicarbonate, brine and dried over sodium sulfate. After solvent removal 600 mg. (87%) of the title amine was obtained which was used without additional purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:14]([NH:18][OH:19])([CH3:17])([CH3:16])[CH3:15]>>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[N+:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[O-:19])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)NO
Reactant: CCCCOc1ccc(C=O)cc1
Product: CCCCOc1ccc(C=[N+]([O-])C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 4-butoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 96% yield (7.18 g) as a solid, m.p. 68.5° C.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[CH2:2][C@@H:3]([CH2:5][CH2:6][CH:7]=C(C)C)[CH3:4].[BH4-].[Na+].C[OH:17]>>[OH:17][CH2:7][CH2:6][CH2:5][C@@H:3]([CH3:4])[CH2:2][C:1]([O:12][CH3:13])=[O:11]
Reactant: CO
Reactant: COC(=O)C[C@H](C)CCC=C(C)C
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)C[C@H](C)CCCO
Reaction time: 2 h

Procedure:
9.42 g (51 mmol) of methyl (R)-(+)-citronellate (9) are dissolved in 26 ml of methanol and saturated with 2.45 g (51 mmol) of 03 for 1 h at -30° C. Then 3.12 g (82 mmol) of NaBH4 (sic) are added in small portions with stirring. During the highly exothermic reaction, which lasts for 2 h, the temperature is kept between -20° C. and +10° C. Then cooling is discontinued and the mixture is brought to room temperature. A high proportion of the methanol is distilled off and to the residue are added 80 ml of CHCl3. This mixture is added at 0° C. to a vigorously stirred solution of 50 ml of conc. HCl in 100 g of ice. The chloroform phase is washed once with Na2CO3 solution and three times with H2O and is then dried over MgSO4 and concentrated. The crude product is distilled through a bulb tube.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:21]=[CH:20][N:19](C(OC(C)(C)C)=O)[N:18]=2)=[O:15])[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[N:29]1([C:33]([C:35]2[CH:36]=[CH:37][C:38](Cl)=[N:39][CH:40]=2)=[O:34])[CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:29]1([C:33]([C:35]2[CH:36]=[CH:37][C:38]([O:1][C:2]3[CH:3]=[C:4]([CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=3)[C:14]([NH:16][C:17]3[CH:21]=[CH:20][NH:19][N:18]=3)=[O:15])=[N:39][CH:40]=2)=[O:34])[CH2:32][CH2:31][CH2:30]1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Reactant: O=C(c1ccc(Cl)nc1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 160 °C
Yield: 11.6 %

Procedure:
A solution of 1,1-dimethylethyl 3-{[(3-hydroxy-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}phenyl)carbonyl]amino}-1H-pyrazole-1-carboxylate (157 mg, 0.4 mmol) and 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (95 mg, 0.48 mmol) in acetonitrile (2 mL), containing potassium carbonate (111 mg, 0.8 mmol), was heated in a microwave reactor at 160° C. for 6 hours. The reaction mixture was filtered and the filtrate evaporated to dryness under reduced pressure and purified by chromatography on silica, eluting with 50-100% ethyl acetate in hexane to give a product which was further purified by chromatography on silica, eluting with 0-8% methanol in ethyl acetate, to give the required product as a white foam (21 mg).
Reaction SMILES: Br.C(O)(=O)C.CS(O)(=O)=O.C(OC([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[NH:38])[NH2:37])=[CH:32][C:31]=1[C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:28])=O)C1C=CC=CC=1>C(OCC)C>[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[NH:37])[NH2:38])=[CH:32][C:31]=1[C:39](=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:28]
Reactant: N=C(N)c1ccc(OC(=O)CCCCCNC(=O)OCc2ccccc2)c(C(=O)c2ccccc2)c1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: N=C(N)c1ccc(OC(=O)CCCCCN)c(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To 8.0 ml of a 30% hydrogen bromide-acetic acid mixture, was added 1.7 g of 4-amidino-2-benzoylphenyl 6-benzyloxycarbonylaminocaproate methanesulfonate. The mixture was stirred for one hour at room temperature, whereby the crystals dissolved in 4 to 5 minutes, forming a uniform solution. Upon addition of anhydrous ethyl ether to the solution, an oily substance separated out. The supernatant was removed and the oily substance was washed a few times with ethyl ether. The oily substance was dissolved with heating in a small volume of water, admixed with acetone, and stirred while cooling in ice, to obtain 0.9 g of a colorless powder of 4-amidino-2-benzoylphenyl 6-aminocaproate dihydrobromide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9])[CH:6]=[CH:7][CH:8]=1
Reactant: C=C1CC(=O)O1
Reactant: Nc1cccc(Br)c1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1cccc(Br)c1
Yield: 49.4 %

Procedure:
To a heated (80° C., oil bath temperature) solution of 20.00 g (0.12M) of m-bromoaniline in 200 mL of dry toluene was added dropwise over a period of 30 min. 12 g (0.14M) of diketene in 100 mL of dry toluene. When the addition was completed, the reaction mixture was brought to reflux for 5 h. The toluene was then removed in vacuo, resulting in a yellow solid. Recrystallisation from toluene afforded 14.70 g (48%) of product as light pink crystals: mp 94°-95° C.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[C:16](=[O:19])[CH2:17][CH2:18][C:14]=3[N:13]=[C:12]2[CH:20]([CH3:22])[CH3:21])=[CH:6][CH:5]=1>ClCCl.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:15]3[CH:16]([OH:19])[CH2:17][CH2:18][C:14]=3[N:13]=[C:12]2[CH:20]([CH3:22])[CH3:21])=[CH:8][CH:9]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CC2
Reaction time: 3 h
Yield: 93.1 %

Procedure:
Sodium borohydride (76 mg) was added to a stirred solution of Intermediate 18 (290 mg) in dichloromethane (3 ml) and methanol (3 ml). The reaction mixture was stirred for 3 hours. The reaction mixture was concentrated under vacuum, partitioned between EtOAc (20 ml) and water (15 ml). The two phases were separated and the aqueous phase was extracted again with EtOAc (2×10 ml). The phases were separated, the organic extracts were combined, dried (hydrophobic frit) and concentrated under vacuum to give the title compound (272 mg). LC/MS MH+ 291, Rt 1.35 min (5 minute run).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:6]=1[C:7]([O:9]CCC)=[O:8])[CH2:2][CH3:3].CC(C)([O-])C.[K+].CCCCCC.C(OCC)(=O)C.Cl>CS(C)=O>[CH2:1]([O:4][C:5]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:6]=1[C:7]([OH:9])=[O:8])[CH2:2][CH3:3]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)OCCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCc1cccc(OCCC)c1C(=O)O
Temperature: 70 °C
Yield: 8.1 %

Procedure:
To a stirred solution of Propyl 2-propoxy-6-pentadecylbenzoate (10 g, 240 mmol) in dimethyl sulfoxide (40 mL) was added potassium tert-butoxide (10 g, 890 mmol) in portions. The solution was heated to 70° C. on a water bath for 2 h, and the progress of the reaction was monitored by TLC using a hexane-ethyl acetate (8:2) solvent system. The reaction mass was cooled to 10° C., poured into ice water, and then acidified with 5% dilute hydrochloric acid. The precipitated solid was filtered and washed thoroughly with distilled water, and the crude mass was recrystallized in hexane (50 mL) to yield an off-white solid of 2-Propoxy-6-pentadecylbenzoic Acid (7.6 g, 80%).