Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:18])(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccncc1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Product: O=C(Nc1ccncc1)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and 4-aminopyridine (52 mg, 0.55 mmol) using method C. The residue was purified using flash chromatography eluting with 30-90 EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 3-(indolin-1-ylsulfonyl)-N-(pyridin-4-yl)benzamide as an off-white solid. Yield: 86 mg (43%). 1H-NMR: 10.81 (s, 1H), 8.50 (d, J=6.0 Hz, 2H), 8.35 (t, J=1.5 Hz, 1H), 8.24 (dt, J=8.0, 1.0, 1.0, 1H), 8.01 (dt, J=8.0, 1.0, 1.0, 1H), 7.77-7.72 (m, 3H), 7.50 (d, J=8.0 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 3.98 (t, J=8.5 Hz, 2H), 2.91 (t, J=8.5 Hz, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:26][S:27]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:24][CH:25]=1)(=[O:29])=[O:28]
Reactant: NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 54.5 %

Procedure:
1-[1-(4-Aminomethylphenethyl)piperidin-4-yl]indoline (0.120 g) and methanesulfonyl chloride (0.030 ml) were treated as in Example 36 to give the title compound (0.078 g) as a pale yel low oil (yield: 54.5%).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]([F:24])([F:23])[C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[C:13]([OH:15])=[O:14]>C1(C)C=CC=CC=1.CO>[CH3:1][O:14][C:13](=[O:15])[C:12]1[CH:11]=[C:10]([C:9]([F:23])([F:24])[F:8])[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trimethylsilyldiazomethane (11.5 mL) was added drop-wise to a solution of 3,5-bis-(trifluoromethyl)benzoic acid (2 g) in dry toluene (20 mL) and methanol (0.5 mL) previously cooled to 0° C. under a nitrogen atmosphere. The solution was stirred at r.t. for 1 hr, then concentrated in vacuo to give 3,5-bis-(trifluoromethyl)-benzoic acid methyl ester (2 g) as a colourless oil. A solution of 3,5-bis-(trifluoromethylybenzoic acid methyl ester (2 g) and 1-vinyl-2-pyrrolidinone (863 μL) was added to a mixture of sodium hydride (60% suspension in mineral oil—0.41 g) in dry toluene (30 mL) previously heated to reflux. The mixture was stirred for 12 hrs, then it was partitioned between saturated ammonium chloride solution and AcOEt. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (CH/AcOEt 8:2) to give the title compound (1.6 g) as a beige oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Fc1cccc(-c2csc(C3CCNCC3)n2)c1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnn1)N1CCC(c2nc(-c3cccc(F)c3)cs2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 43.8 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (250 mg, 0.922 mmol), 4-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperidine (220 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.8 ml) was stirred at 70° C. for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (141 mg, 43.7%) as a solid.
Reaction SMILES: [CH2:1]([N:8]([C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:23])[C@@H:9]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]([C@H:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH3:23])[C@@H:9]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[C@@H](CC(=O)OC(C)(C)C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC[C@@H](CC(=O)O)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Yield: 165.1 %

Procedure:
The product from step (ii) (12 g) was dissolved in DCM (40 mL) and TFA (2 mL) and the reaction mixture stirred for 24 h. The solvents were evaporated to give the subtitle compound 17 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[C:8]([C:13]([OH:15])=O)=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:16][C:17]1([NH:23][C:24]2[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:21][CH2:20][CH2:19][CH:18]1[NH2:22].N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:16][C:17]1([NH:23][C:24]2[N:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][N:29]=2)[CH2:21][CH2:20][CH2:19][CH:18]1[NH:22][C:13]([C:8]1[C:7]([C:2]2[N:1]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:15]
Reactant: O=C(O)c1ncccc1-c1ncccn1
Reactant: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1N
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-c1ncccn1

Procedure:
A solution of 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 80 mg, 0.40 mmol), 1-methyl-1-N-[5-(trifluoromethyl)pyrimidin-2-yl]cyclopentane-1,2-diamine (Intermediate 50; 103 mg, 0.40 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (81 mg, 0.60 mmol), EDC (114 mg, 0.60 mmol) and DIPEA (0.208 ml, 1.19 mmol) in DCM (4 ml) was stirred at room temperature for 4 days. The reaction was diluted with DCM (5 ml) and a saturated solution of sodium bicarbonate (5 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by reverse phase chromatography (C18 silica, 5-95% water (0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].C(Cl)(Cl)Cl.[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]([C:29](Cl)=[O:30])[C:22]2[O:27][CH2:26][CH2:25][O:24][C:23]=2[CH:28]=1)(=[O:18])=[O:17]>C(Cl)(Cl)Cl.O>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:29]([C:21]1[C:22]2[O:27][CH2:26][CH2:25][O:24][C:23]=2[CH:28]=[C:19]([S:16](=[O:18])(=[O:17])[NH:15][CH3:14])[CH:20]=1)=[O:30])[CH3:2]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Reactant: CCN1CCCC1CN
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC)cc2c1OCCO2
Yield: 66.1 %

Procedure:
82 g of dextrorotatory 1-ethyl-2-aminomethylpyrrolidine, 600 ccm of chloroform and, gradually, at a temperature of from 5°-10° C.; 200 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were introduced into a balloon flask with an agitator and a thermometer. After the addition of a liter of water chloroform was distilled and then the remaining solution was filtered. The base was precipitated by the addition of 60 cm3 of 20% ammonia. The crystals formed were dried off, washed with water and then dried. 162 g of dextrorotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 136°-137° C.; yield: 66%).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[C:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:5]=1>[OH-].[Na+]>[O:15]([C:7]1[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][C:6]=1[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CNS(=O)(=O)c1cc(C(=O)OC)cc(N2CCCC2)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CNS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1

Procedure:
54 g of the methyl ester obtained according to (b) are suspended in 50 ml of 1 N NaOH and heated, while stirring, on the steam bath. When a clear solution has formed, the whole is allowed to cool and the free acid is precipitated with the aid of 1 N-HCl. The 4-phenoxy-3-(1-pyrrolidinyl)-5-methylsulphamoylbenzoic acid melting at 245°-248° C. with decommposition is obtained by recrystallisation from methanol/water.
Reaction SMILES: [N:1]([O-])=O.[Na+].[ClH:5].C(OC([N:11]1[C:15]([NH2:16])=[C:14]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[N:12]1)C)C.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:5][C:17]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:1][N:16]=[C:15]2[NH:11][N:12]=[CH:13][C:14]=12
Reactant: Cl
Reactant: O=N[O-]
Reactant: CCOC(C)n1ncc(C#Cc2ccccc2)c1N
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Clc1c(-c2ccccc2)nnc2[nH]ncc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium nitrite (4.3 g, 63 mmol) was added to conc. HCl (314 mL) at −15° C. and stirred for 10 min. 1-(1-ethoxyethyl)-4-(phenylethynyl)-1H-pyrazol-5-amine (3 g, 31.4 mmol) was added and the mixture stirred at −10° C. for 10 min and room temperature for 1 d. The reaction mixture was cooled to 0° C. and CH2Cl2 (250 mL) was added. Under vigorous stirring, Na2CO3 (160 g) was added carefully followed by sat. aq. NaHCO3 solution over a period of 2 h until the pH was 7 and there was no more foaming on further addition of base. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, iso-hexanes/diethyl ether 1:0 to 0:1) yielding the title compound as a solid (3.43 g).
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH:18]=[C:9]([C:10](=[O:12])[CH3:11])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)c1ccccc1
Product: CC(=O)C(=CN(C)C)C(=O)c1ccccc1
Temperature: 80 °C

Procedure:
A stirred mixture of benzoylacetone (16.2 g) and dimethylformamide dimethylacetal (16.2 ml) was heated on an oil bath at 80° C. for 40 minutes. Volatile materials were removed under vacuum and the residue was crystallised from ether to give 2-(dimethylaminomethylene)-1-phenyl-1,3-butanedione (mp 81°-83° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][CH:4]=1)#[N:2].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+]>CN(C)C=O.CCOCC>[N:2]1[NH:19][N:20]=[N:21][C:1]=1[C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(-c2nn[nH]n2)cc1
Temperature: 110 °C
Yield: 91.2 %

Procedure:
A mixture of tert-butyl [(1S)-1-(4-cyanophenyl)ethyl]carbamate (step 1, 1.11 g, 4.51 mmol), sodium azide (1.75 g, 27.1 mmol) and ammonium chloride (1.15 g, 27.1 mmol) in N,N-dimethylforamide (25 mL) was heated at 110° C. for 24 h. After cooling to room temperature, the mixture was diluted with ether (200 mL) and washed with 1 N hydrochloric acid (100 mL). The organic layer was dried over magnesium sulfate and evaporated. The residue was crystallized from dichloromethane and hexane to give 1.19 g (91%) of the title compounds as white solids: 1H-NMR (DMSO-d6) δ 7.98 (2H, d, J=8.3 Hz), 7.51 (2H, d, J=8.3 Hz), 4.74–4.63 (1H, m), 1.37–1.32 (12H, m); MS (ESI) m/z 290 (M+H)+, 288 (M−H)−.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[S:37]([CH3:40])(=[O:39])=[O:38])[N:27]=[C:26]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]2[CH3:47])[N:25]=1.[F:48][CH:49]([F:70])[CH2:50][NH:51][C:52]([NH:54][C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[CH:57][CH:56]=1)=[O:53]>>[F:48][CH:49]([F:70])[CH2:50][NH:51][C:52]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([C:24]2[CH:29]=[C:28]([C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[S:37]([CH3:40])(=[O:39])=[O:38])[N:27]=[C:26]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][C@@H:42]3[CH3:47])[N:25]=2)=[CH:57][CH:56]=1)=[O:53]
Reactant: CC1(C)OB(c2ccc(NC(=O)NCC(F)F)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCC(F)F)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Yield: 23 %

Procedure:
Method as described for intermediate 5 using (S)-4-(4-chloro-6-(5-fluoro-2-(methylsulfonyl)phenyl)pyrimidin-2-yl)-3-methylmorpholine (intermediate 16) and 1-(2,2-difluoroethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 20). Purification was achieved using flash chromatography (20-90% EtOAc in petroleum ether (40:60). The material was further purified by prep HPLC (low pH) to afford a white solid (20 mg, 23%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[OH:8][CH2:9][CH2:10][N:11]([CH2:16][CH2:17][OH:18])[C:12](=[O:15])[CH2:13][OH:14]>>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([O:8][CH2:9][CH2:10][N:11]([CH2:16][CH2:17][O:18][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[C:12](=[O:15])[CH2:13][O:14][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:4]
Reactant: O=C(CO)N(CCO)CCO
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)OCCN(CCOC(=O)C(C)(C)C)C(=O)COC(=O)C(C)(C)C

Procedure:
This compound was prepared from 73 g (0.6 mole) of trimethylacetyl chloride and 32.6 g (0.2 mole) of N,N-bis(hydroxyethyl)hydroxyacetamide by the procedure of Example 1. Its structure was established by infrared and nuclear magnetic resonance spectroscopy. It was a white solid with m.p. 51.4° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:7]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[N:8][C:9]([NH2:13])=[N:10][C:11]=1[CH3:12].[CH:20]([C:22]1[CH:23]=[C:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:25]=[CH:26][CH:27]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[NH2:13][C:9]1[N:10]=[C:11]([CH3:12])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:20][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:25]=[CH:26][CH:27]=2)=[C:7]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:8]=1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCCN
Reactant: COC(=O)Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCNc1nc(N)nc(C)c1CCCCNCc1cccc(CC(=O)OC)c1
Reaction time: 72 h
Yield: 6.2 %

Procedure:
To the product of step (ii) (0.06 g), methyl 2-(3-formylphenyl)acetate (0.0403 g) and acetic acid (0.0136 g) in THF (10 mL) was added sodium triacetoxyborohydride (0.1102 g). The reaction mixture was stirred for 72 h, the solvents were evaporated and the residue dissolved in MeOH, acidified and purified via SCX resin, then RPHPLC to give the title compound 6 mg.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][C:12]([O:18][C@@H:19]4[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]([OH:28])[C@H:20]4[OH:29])=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3]([OH:30])[CH:2]=1.[C:31]([O-])(=[O:36])[CH2:32][C:33]([O-:35])=[O:34].CS(C)=[O:40]>>[CH:5]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([O:18][C@@H:19]4[O:24][C@H:23]([CH2:25][O:26][C:31]([CH2:32][C:33]([OH:35])=[O:34])=[O:36])[C@@H:22]([OH:27])[C@H:21]([OH:28])[C@H:20]4[OH:29])=[CH:13][C:14]=3[OH:40])[O:9][CH:8]=2)=[CH:1][CH:2]=[C:3]([OH:30])[CH:4]=1
Reactant: O=C([O-])CC(=O)[O-]
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc12
Reactant: CS(C)=O
Product: O=C(O)CC(=O)OC[C@H]1O[C@@H](Oc2cc(O)c3c(=O)c(-c4ccc(O)cc4)coc3c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The 13C nuclear magnetic resonance spectrum (NMR) of daidzin malonate in dimethyl sulfoxide (DMSO-d6) at 20° C. shows the following characteristic signals:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:22]I.[H-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[CH2:12]([O:11][CH2:10][C@H:9]([N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH3:22])[C:19]([OH:21])=[O:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)[C@@H](COCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
N-Boc-O-Benzyl-L-Serine (8.86 g, 30.0 mmol) was dissolved in tetrahydrofuran (94 mL) and the resultant solution was cooled with a 0° C. ice bath. Methyl iodide (15.0 mL, 241 mmol) was added in one portion. After 5 min, sodium hydride (60% dispersion in mineral oil, 3.6 g, 90 mmol) was added in three portions during 10 min. The resultant reaction mixture was stirred under nitrogen for 76 h while the cooling bath temperature was maintained at 0° C. The reaction mixture was diluted with cold (0-5° C.) ethyl acetate (150 mL) and water (1.5 mL) was added dropwise over 10 min. The cooling bath temp was allowed to slowly warm to ambient temperature overnight. The reaction mixture was concentrated to a viscous oil on a rotary evaporator without heating. The residue was partitioned between ether (100 mL) and water (300 mL). The ethereal layer was further washed with saturated aqueous sodium bicarbonate (150 mL). The combined aqueous portions were acidified to pH 3 using aqueous citric acid (2 M) and were extracted with ethyl acetate (3×150 mL). The combined extracts were washed with water (2×150 mL) and 5% aqueous sodium thiosulfate (150 mL), dried over magnesium sulfate and concentrated on a rotary evaporator (without heating) to afford (S)-3-Benzyloxy-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid as viscous, colorless oil (8.98 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[N:10]([CH2:19][CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][C:3]=1[CH:35]=[O:36].[CH3:37]Br.[Mg].[Cl-].[NH4+]>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[N:10]([CH2:19][CH2:20][CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:4][C:3]=1[CH:35]([OH:36])[CH3:37]
Reactant: O=Cc1cc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)ccc1Cl
Reactant: CBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cc(NC(=O)N(CCC(c2ccccc2)c2ccccc2)CCN2CCOCC2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
16 mg (0.033 mmol, 1 eq.) of 3-(4-chloro-3-formylphenyl)-1-(3,3-diphenylpropyl)-1-(2-morpholin-4-ylethyl)urea (obtained in Example 63) are dissolved in 0.7 mL of dry THF. Once the solution has been cooled to 0° C., 17 μL (0.049 mmol, 1.5 eq.) of magnesium methyl bromide in solution (3 M in diethyl ether) are added to the medium. After stirring for 20 min. at 0° C., the reaction is neutralised with a saturated ammonium chloride solution at 0° C. The aqueous phase is extracted with dichloromethane, the organic phases are washed with brine, dried over MgSO4, filtered and concentrated. The crude reaction product is subjected to chromatography over silica gel (eluent: 1/1 heptane/AcOEt). 11.4 mg of expected product are obtained (yield=67%).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[CH3:10][C:11]1[O:15][N:14]=[C:13]([NH2:16])[CH:12]=1.[NH:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][C:20](O)=[O:21].C(Cl)[Cl:31]>CN(C1C=CN=CC=1)C>[ClH:31].[NH2:17][CH2:18][CH2:19][C:20]([NH:16][C:13]1[CH:12]=[C:11]([CH3:10])[O:15][N:14]=1)=[O:21]
Reactant: Cc1cc(N)no1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: ClCCl
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Product: Cc1cc(NC(=O)CCN)no1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of DMAP (9.77 g), TEA (55.23 ml) and N,N′-diisopropylcarbodiimide (49.01 ml) in DCM is treated with 5-methyl-isoxazole-3-ylamine (28.8 g) and Boc-β-Ala-OH (50 g) and stirred at room temperature for 18 h. The resulting mixture is diluted with DCM (1750 ml) and washed with 10% citric acid (2×500 ml), saturated sodium hydrogen carbonate solution (2×500 ml), and brine (600 ml). The organic portion is dired (MgSO4), concentrated in vacuo and the crude residue is stirred with iso-hexane (750 ml) for 1 hr. The resulting solid is dissolved in dioxane (400 ml) and treated with 4M HCl in dioxane (350 ml). After 1 hr the precipitate is filtered off and washed with dioxane (100 ml) to afford the 3-amino-N-(5-methyl-isoxazol-3-yl)-propionamide hydrochloride. (MH+ 169.84)
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.N>CC(N(C)C)=O.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:16]3[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: OC1CCNCC1
Reactant: Fc1ccc2nnc(Cl)n2c1
Agent: N
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: OC1CCN(c2nnc3ccc(F)cn23)CC1
Yield: 43.7 %

Procedure:
A brown solution of Intermediate 24b (855 mg, 4.98 mmol) and 4-hydroxypiperidine (2.02 g, 19.9 mmol) in DMA (15 mL) was irradiated to 175° C. in the microwave for 3 h. The cooled solution was concentrated in vacuo, then the residue diluted with water (20 mL) and brine (20 mL). The mixture was washed with diethyl ether (2×50 mL), then extracted with EtOAc (2×50 mL). The combined EtOAc layers were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave a yellow oil. The aqueous was further extracted with DCM (3×50 mL). The combined DCM layers were passed through a hydrophobic frit and concentrated in vacuo to leave a brown oil. The two oils were combined. FCC, using 4-5% [2M NH3 in MeOH] in DCM, gave the title compound as a yellow crystalline solid (514 mg, 44%). LCMS (Method 3): Rt 1.96 min, m/z 237 [MH+].