Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:4][CH:3]1[C:5](=O)[CH2:6][C:7]#[N:8].[NH2:11][NH2:12]>CCO>[F:1][C:2]1([F:10])[CH2:4][CH:3]1[C:5]1[NH:12][N:11]=[C:7]([NH2:8])[CH:6]=1
Reactant: N#CCC(=O)C1CC1(F)F
Reactant: NN
Solvent: CCO
Product: Nc1cc(C2CC2(F)F)[nH]n1
Yield: 78.5 %

Procedure:
To a solution of MeCN (1.1 g, 16.8 mmol) in THF (60 mL) was added dropwise n-BuLi in THF (11.2 mL, 40.3 mmol) at −78° C., and the reaction mixture was stirred at −78° C. under N2 for 30 min. Butyl 2,2-difluorocyclopropanecarboxylate (3.0 g, 16.8 mmol) was added at −78° C., and the reaction mixture was allowed to warm to RT over 3 h. The reaction mixture was quenched with water and adjusted to pH 7 with 1N HCl. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford crude 3-(2,2-difluorocyclopropyl)-3-oxopropanenitrile. A mixture of crude 3-(2,2-difluorocyclopropyl)-3-oxopropanenitrile and hydrazine (2.0 g, 50.4 mmol, 85% pure) in EtOH (30 mL) was stirred at reflux for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue was purified by chromatography eluting with an EtOAc/petroleum ether gradient (12.5 to 100% EtOAc) to afford 2.1 g (78.5%) of 45 as a yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 11.40 (br s, 1H), 5.26 (s, 1H), 4.80 (br s, 2H), 2.78-2.66 (m, 1H), 2.04-1.75 (m, 1H), 1.73-1.21 (m, 1H); MS (ESI+) m/z=160.1 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[NH:9][CH2:10][C:4]=2[CH:3]=1.[CH2:16]([C:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]=1[CH2:27][N:28]([CH3:33])[C:29](=[O:32])[CH:30]=[CH2:31])[CH3:17].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:8]1([CH3:12])[C:7](=[O:13])[NH:6][C:5]2[N:14]=[CH:15][C:2](/[CH:31]=[CH:30]/[C:29]([N:28]([CH2:27][C:19]3[O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:18]=3[CH2:16][CH3:17])[CH3:33])=[O:32])=[CH:3][C:4]=2[CH2:10][NH:9]1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1CC
Reactant: CC1(C)NCc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: CN(C)C=O
Product: CCc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNC(C)(C)C(=O)N3)oc2ccccc12
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
To 7-bromo-3,3-dimethyl-1,3,4,5-tetrahydro-pyrido[2,3-e][1,4]diazepin-2-one (400 mg, 1.48 mmol) in propionitrile (40 mL) and DMF (10 mL) was added N-(3-ethyl-benzofuran-2-ylmethyl)-N-methylacrylamide (410 mg, 1.62 mmol), (i-Pr)2EtN (0.51 mL, 2.96 mmol), Pd(OAc)2 (332 mg, 0.148 mmol) and P(o-tol)3 (90.1 mg, 0.296 mmol), and the mixture was de-oxygenated with argon for 15 min. The mixture was heated to reflux overnight, allowed to cool and then filtered. The filtrate was concentrated and the residue was dissolved in CH2Cl2 (150 mL). The organic solution was washed with water and brine, dried (Na2SO4) and the solvent was removed in vacuo. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 20:1) gave the title compound (130 mg, 20%) as an off-white solid: MS m/z 433 (M+H)+.
Reaction SMILES: [FH:1].NC(N)=O.[O:6]1[C@H:8]2[CH2:9][C@H:10]3[C@:25]([CH3:27])([CH2:26][C@@H:7]12)[C@@H:24]1[C@H:13]([C@H:14]2[C@:21]([CH3:29])([CH2:22][C:23]1=[O:28])[C@@H:17]([C:18](=[O:20])[CH3:19])[CH2:16][CH2:15]2)[CH2:12][CH2:11]3>C(=O)(O)[O-].[Na+]>[F:1][C@H:7]1[CH2:26][C@@:25]2([CH3:27])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:24]2[C:23](=[O:28])[CH2:22][C@@:21]2([CH3:29])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C:18](=[O:20])[CH3:19])[CH2:9][C@@H:8]1[OH:6]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: F
Agent: NC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](F)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous hydrofluoric acid (50 ml.) was added slowly to urea (40 g.) to give a colourless liquid. To 11 ml. of the liquid was added 2α,3α-epoxy-5α-pregnane-11,20-dione (650 mg.), and the clear solution was stirred at room temperature overnight. It was poured into saturated sodium bicarbonate solution (250 ml), and the white precipitate was extracted into chloroform. The organic solution was washed with water, dried over sodium sulphate and evaporated to give a white foam (565 mg.). Recrystallisation from acetonepetrol gave the title compound m.p. 174°-178°, [α]D α+114°.
Reaction SMILES: [CH2:1]([C@H:4]1[O:6][C@@H:5]1[C:7]([OH:9])=O)[CH2:2][CH3:3].[CH:10]1([NH2:13])[CH2:12][CH2:11]1.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH:10]1([NH:13][C:7]([C@@H:5]2[C@@H:4]([CH2:1][CH2:2][CH3:3])[O:6]2)=[O:9])[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: CCC[C@H]1O[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCC[C@H]1O[C@@H]1C(=O)NC1CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
(2S,3R)-3-Propyl-2-oxiranecarboxylic acid (1.16 g, 7.8 mmol), methylene chloride (10 ml) and cyclopropylamine (8.5 equivalents) were mixed, and the mixture was cooled to 5° C. A methylene chloride solution (5 ml) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.23 g, 1.2 equivalents) was gradually added thereto, and the mixture was stirred for 2 hours from 5° C. up to room temperature. The organic layer was washed with water (5 ml), 1 N HCl (5 ml) and water (5 ml); and was dried with anhydrous magnesium sulfate. The inorganic products were separated by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound as a pale yellow solid (0.70 g, yield: 53%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12]C)[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=1.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([C:30]([C:32]2[N:33]([CH3:37])[CH:34]=[N:35][CH:36]=2)=[O:31])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[N:29]=[CH:28][C:27]([C:30]([OH:31])([C:32]2[N:33]([CH3:37])[CH:34]=[N:35][CH:36]=2)[C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)=[CH:26][CH:25]=1
Reactant: CCOc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)nc1
Product: CCOc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1

Procedure:
Following the same procedure as that described in example 1E, 6-bromo-4-(3-ethoxy-phenyl)-2-methoxy-quinoline (2 g, 5.59 mmol) and (6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (1.48 g, 6.70 mmol) generated the title compound of 26A (1.458 g, 52% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])=[CH:5]2.[CH:24]12[CH2:29][CH:28]1[CH2:27][N:26]([CH2:30][CH2:31][CH2:32]OC1C=C3C(=CC=1)NC(C(N1CCOCC1)=O)=C3)[CH2:25]2.FC(F)(F)COS(C(F)(F)F)(=O)=O>>[CH:24]12[CH2:29][CH:28]1[CH2:27][N:26]([CH2:30][CH2:31][CH2:32][O:1][C:2]1[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])=[CH:5]3)[CH2:25]2
Reactant: O=C(c1cc2cc(OCCCN3CC4CC4C3)ccc2[nH]1)N1CCOCC1
Reactant: O=C(c1cc2cc(O)ccc2n1CC(F)(F)F)N1CCOCC1
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: O=C(c1cc2cc(OCCCN3CC4CC4C3)ccc2n1CC(F)(F)F)N1CCOCC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 1, the title compound was synthesized from {5-[3-(3-aza-bicyclo[3.1.0]hex-3-yl)-propoxy]-1H-indol-2-yl}-morpholin-4-yl-methanone (Example 5, step 4) and 2,2,2-trifluoroethyl-trifluoromethanesulfonate. The title product was obtained in 45% yield as white solid. MS (m/e): 452.5 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12])=[O:4].[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12])=[O:4]
Reactant: Oc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc(OC)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1S(=O)(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C

Procedure:
N-(3,4-Dimethoxybenzenesulfonyl)-[(2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid] methyl ester (8) (1.00 g, 2.90 mmol), phenol (0.41 g, 4.34 mmol) and triphenylphosphine (1.14 g, 4.34) are combined in THF (10 mL). The mixture is cooled in an ice-bath and diethyl azodicarboxylate (0.76 g, 4.34 mmol) is added dropwise over 30 minutes. The reaction is allowed to warm to ambient temperature with overnight stirring. The reaction mixture is concentrated at reduced pressure and treated with ether. The mixture is decanted and the organic extract is concentrated. The residue is purified via silica gel chromatography (40% ethyl acetate in hexanes) affording the desired product as a solid. CIMS: MH+ 422
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[S:9][C:10]([C:13](=[O:24])[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)=[CH:11][CH:12]=1)=[O:7])C.Cl>C(O)C>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[CH2:15][NH:14][C:13]([C:10]1[S:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=1)=[O:24]
Reactant: CCOC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Yield: 83 %

Procedure:
Aqueous 1M sodium hydroxide (16.3 mL; 16.3 mmole) was added to a stirring, solution of (12(a)) (1.17g; 3.3 mmole) in ethanol (70 mL). The reaction mixture was and adjusted to pH 2 by addition of 2M hydrochloric acid. The filtered solid was washed with water and dried in vacuo to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carboxylic acid (12(b)) as a white solid (83%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH:15]([CH3:17])[CH3:16])[CH3:2].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]([CH3:39])=[C:35]([CH2:37]Cl)[N:36]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C(C1C=CC(C=O)=CC=1)(C)(C)C.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:37][C:35]2[N:36]=[C:32]([C:29]3[CH:28]=[CH:27][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:31][CH:30]=3)[O:33][C:34]=2[CH3:39])=[CH:9][C:8]=1[O:14][CH:15]([CH3:16])[CH3:17])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OC(C)C)OCC
Reactant: Cc1oc(-c2ccc(C(C)(C)C)cc2)nc1CCl
Agent: CC(C)(C)c1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(C(C)(C)C)cc3)oc2C)cc1OC(C)C)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(4-hydroxy-2-isopropoxy-phenyl)-propionic acid ethyl ester was reacted with 2-(4-tert-butyl-phenyl)-4-chloromethyl-5-methyl-oxazole (prepared from 4-tert-butyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 5 a] and 2 b]) in N,N-dimethylformamide in the presence of potassium carbonate to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-isopropoxy-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 g], to yield [rac]-3-{4-[2-(4-tert-butyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-isopropoxy-phenyl}-2-ethoxy-propionic acid as colorless viscous oil, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([Cl:42])[CH:41]=1>>[Cl:35][C:36]1[CH:37]=[C:38]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)[CH:39]=[C:40]([Cl:42])[CH:41]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(Cl)cc(Cl)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3,5-dichloro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.96 (d, J=6.60 Hz, 6H), 1.58 (dt, J=13.45, 6.72 Hz, 1H), 1.77 (ddd, J=13.76, 7.34, 7.03 Hz, 1H), 2.09 (ddd, J=13.45, 7.83, 7.58 Hz, 1H), 3.83 (t, J=7.70 Hz, 1H), 7.38 (t, J=1.83 Hz, 1H), 7.48 (d, J=1.71 Hz, 2H), 7.52 (s, 1H), 7.57-7.67 (m, 2H), 7.71-7.77 (m, 4H); Calcd for C25H21Cl2F3O2 (M+H) 482.33, Found 482.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([P:7]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:8][P:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.BrCCBr.[OH-:32].[Na+].[Na+].[I-]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[P:7]([CH2:8][P:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:32])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: c1ccc(P(CP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: [OH-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: BrCCBr
Product: O=P(CP(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
A mixture of palladium acetate (5 mg; 2.2×10-2 mmol), dppm (2.00 g; 5.21 mmol), 1,2-dibromoethane (2.0 g; 10.64 mmol), and dichloromethane (10 mL) was stirred for 20 minutes. To this solution, aqueous NaOH (20% by weight; 6 mL) containing NaI (40 mg; 0.27 mmol) was added and the mixture was vigorously stirred under reflux for 4 hours. The organic phase was filtered through a silica plug which was then washed with CH2Cl2 /AcOEt (3:1 by volume). The combined organic solutions were evaporated to dryness. The solid residue was dissolved in the minimum amount of boiling CH2Cl2, the warm solution was treated with ether (100 mL; portionwise) and left at room temperature for 2 hours. Slightly yellowish fluffy needles of spectroscopically and TLC pure dppmO were separated, washed with ether, and dried under vacuum. The yield was 1.53 g (74%). 1H NMR (CDCl3, 20° C.), δ: 3.1 (d, 2H, J=12.7 Hz, CH2); 7.1-7.9 (m, 20H, Ph). 31P NMR (CDCl3, 20° C.), δ: -26.5 (d, 1P, JP-P =50.5 Hz, PPh2); 29.8 (d, 1P, JP-P =50.5 Hz, P(O)Ph2).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:13]1[S:19][C:17](=[O:18])[NH:16][C:14]1=[O:15]>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[C:13]3[S:19][C:17](=[O:18])[NH:16][C:14]3=[O:15])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: Cn1nnc2ccc(C=O)cc21
Reactant: O=C1CSC(=O)N1
Product: Cn1nnc2ccc(C=C3SC(=O)NC3=O)cc21

Procedure:
Following the general method as outlined in Example 1, starting from 3-Methyl-3H-benzotriazole-5-carbaldehyde (intermediate 34) and thiazolidinedione, the title compound was obtained.
Reaction SMILES: [C:1]1([C@@:7]2([CH3:29])[C:11](=[O:12])[N:10]([C@@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([O-])=[O:15])[C:9](=[O:21])[N:8]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:30][C@H:31]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=1[O:48][CH3:49])[CH2:32][C:33]([O:35]C(C)(C)C)=[O:34].FC(F)(F)C(O)=O>>[C:1]1([C@@:7]2([CH3:29])[C:11](=[O:12])[N:10]([C@@H:13]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:14]([NH:30][C@H:31]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3[O:48][CH3:49])[CH2:32][C:33]([OH:35])=[O:34])=[O:15])[C:9](=[O:21])[N:8]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@@H](C(=O)[O-])N1C(=O)N(Cc2ccccc2)[C@@](C)(c2ccccc2)C1=O
Reactant: COc1ccc([C@@H](N)CC(=O)OC(C)(C)C)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc([C@H](CC(=O)O)NC(=O)[C@H](CC(C)C)N2C(=O)N(Cc3ccccc3)[C@@](C)(c3ccccc3)C2=O)c(OC)c1

Procedure:
(by reaction of 169.5 with tert-butyl (S)-3-amino-3-(2,4-dimethoxyphenyl)propionate and subsequent cleavage of the tert-butyl ester with trifluoroacetic acid)
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][C:6]1[S:10][C:9](B(O)O)=[CH:8][CH:7]=1)[CH3:3].Br[C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([C:24]([NH2:26])=[O:25])[CH:23]=1)[NH:20][CH:19]=[C:18]2[CH:27]1[CH2:32][CH2:31][N:30]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:36]([S:33]([N:30]1[CH2:29][CH2:28][CH:27]([C:18]2[C:17]3[C:21](=[C:22]([C:24]([NH2:26])=[O:25])[CH:23]=[C:15]([C:9]4[S:10][C:6]([CH2:5][NH:4][CH:2]([CH3:3])[CH3:1])=[CH:7][CH:8]=4)[CH:16]=3)[NH:20][CH:19]=2)[CH2:32][CH2:31]1)(=[O:35])=[O:34])[CH3:37]
Reactant: CC(C)NCc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(C)C)s4)cc23)CC1
Yield: 37 %

Procedure:
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), isopropylamine (0.027 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 41 mg of crude (5-{[(1-methylethyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(1-methylethyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give 74 mg of the title compound (37%).
Reaction SMILES: [CH2:1]([OH:34])[C@H:2]1[O:7][CH:6]([O:8][CH2:9][C@H:10]2[O:15][CH:14]([O:16][C@:17]3([CH2:26][OH:27])[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C@@H:18]3[OH:25])[C@H:13]([OH:28])[C@@H:12]([OH:29])[C@@H:11]2[OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@H:3]1[OH:33].O.O.O.O.O>CN(C)C=O>[CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][CH2:9][C@H:10]2[O:15][C@H:14]([O:16][C@:17]3([CH2:26][OH:27])[O:21][C@H:20]([CH2:22][OH:23])[C@@H:19]([OH:24])[C@@H:18]3[OH:25])[C@H:13]([OH:28])[C@@H:12]([OH:29])[C@@H:11]2[OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@H:3]1[OH:33]
Reactant: OC[C@H]1OC(OC[C@H]2OC(O[C@]3(CO)O[C@H](CO)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Solvent: CN(C)C=O
Solvent: O
Product: OC[C@H]1O[C@H](OC[C@H]2O[C@H](O[C@]3(CO)O[C@H](CO)[C@@H](O)[C@@H]3O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Yield: 311.1 %

Procedure:
A solution of 2.0 g of D-raffinose pentahydrate in 50 ml of absolute dimethylformamide was stirred at 60° C. for 20 hours in the presence of 10.3 g of sulphur trioxide-trimethylamine complex, whereby a precipitate separated. The solvent was decanted off. The residue was washed with methanol, dissolved in 64 ml of aqueous 10% sodium acetate solution and concentrated. The residue was taken up several times in water and evaporated to remove trimethylamine. The residue was gel-chromatographed (Sephadex® LH 20) in order to remove salts. After freeze-drying there were obtained 5.28 g of sulfated raffinose, S=19.89%, AS (average degree of sulfation) about 2.8.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][O:20][C:21]2=[O:26]>C(#N)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:16]/[C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][O:20][C:21]3=[O:26])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=C1OCc2c(/N=C/c3ccc(Cl)cc3)cccc21
Yield: 54.9 %

Procedure:
To a stirred mixture of 4-chlorobenzaldehyde (2.3 g, 16.1 mmol) and anhydrous magnesium sulfate (16 g, 134 mmol) in anhydrous acetonitrile (200 ml) was added 4-aminoisobenzofuran-1(3H)-one (2 g, 13.4 mmol) at room temperature. After the addition, the mixture was stirred at reflux for overnight. The mixture was filtered and the cake was washed with ethyl acetate (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether and re-crystallized from ethyl acetate to give the title compound (2 g, yield: 55%). LC-MS (ESI) m/z: 272 (M+1)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C@@H:13]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH3:14])[C@@H:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@@H:7]1[CH:36]=O)(=[O:3])[CH3:2].[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C@@H:13]([C:15]2[CH:16]=[C:17]([C:25]([F:26])([F:28])[F:27])[CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=2)[CH3:14])[C@@H:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@@H:7]1[CH2:36][NH:45][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(=O)OC[C@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)[C@@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(=O)OC[C@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)[C@@H]1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.5 %

Procedure:
A mixture of aldehyde (0.56 g, 1.0 mmol) from Step L, benzylamine (0.15 mL, 1.4 mmol) and sodium triacetoxy borohydride (1.0 g, 4.7 mmol) in 50 mL dimethyl chloride was stirred at room temperature for 12 hr. The mixture was washed with sat. aq. NaHCO3, then brine, dried over MgSO4 and filtered. The solvent was evaporated under vacuum to give an oil (0.61 g), which was used in the next step without purification. MS: (MH)+ 624.5.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH2:5][C@H:4]([CH3:13])[N:3]1[C:14]1[O:15][C:16]2[C:17](=[C:19]([C:23]([O:25]C)=[O:24])[CH:20]=[CH:21][CH:22]=2)[N:18]=1.[Li+].[I-]>N1C=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][N:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH2:5][C@H:4]([CH3:13])[N:3]1[C:14]1[O:15][C:16]2[C:17](=[C:19]([C:23]([OH:25])=[O:24])[CH:20]=[CH:21][CH:22]=2)[N:18]=1
Reactant: COC(=O)c1cccc2oc(N3[C@@H](C)CN(C(=O)N(C)C)C[C@@H]3C)nc12
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: C[C@H]1CN(C(=O)N(C)C)C[C@H](C)N1c1nc2c(C(=O)O)cccc2o1
Temperature: 110 °C

Procedure:
To a solution of methyl 2-((2S,6S)-2,6-dimethyl-4-(dimethylcarbamoyl)piperazin-1-yl)benzoxazole-4-carboxylate (265 mg, 0.74 mmol) in pyridine (5 mL) was added LiI (984 mg, 7.35 mmol). The mixture was heated at 110° C. for 14 h and allowed to cool to ambient temperature. The reaction was partially concentrated under reduced pressure before partitioning with 9:1 CH2Cl2/2-propanol (50 mL) and 1 N HCl (20 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford crude 2-((2S,6S)-2,6-dimethyl-4-(dimethylcarbamoyl)piperazin-1-yl)benzoxazole-4-carboxylic acid as an orange oil which was directly elaborated without purification.