Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([P:4]([CH:6]([CH3:8])[CH3:7])Cl)([CH3:3])[CH3:2].[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1>C1COCC1>[CH:1]([P:4]([CH:6]([CH3:8])[CH3:7])[C:12]1[CH:13]=[CH:14][C:9]([CH3:17])=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CC(C)P(Cl)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(P(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylchlorophosphine (2 mL, 12.57 mmol) in THF (25 mL) at −78° C. was added 4-tolylmagnesium bromide (12.57 mL, 12.57 mmol) dropwise. After 1 h at −78° C., the reaction mixture was let warm to RT. The solvent was removed and material was used without further purification. MS: cal'd 209 (MH+), exp 209 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2([CH3:25])[CH2:24][O:23]2)=[O:21])=[CH:15][C:14]=1[CH3:26]>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:25][C:22]([OH:23])([CH3:24])[C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[C:14]([CH3:26])[CH:15]=2)=[O:21])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1F
Reactant: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(OCC(C)(O)C(=O)Nc2ccc(F)c(C)c2)cc1

Procedure:
3-(4-Acetylaminophenoxy)-N-(4-fluoro-3-methylphenyl)-2-hydroxy-2-methylpropionamide was prepared as described in Example 61 c starting from 4-acetamidophenol and 2-methyloxirane-2-carboxylic acid (4-fluoro-3-methylphenyl)amide. 1H NMR (400 MHz, DMSO-d6): 1.40 (3H, s), 2.00 (3H, s), 2.20 (3H, s), 3.90 (1H, d, J=9.5 Hz), 4.15 (1H, d, J=9.5 Hz), 6.03 (1H, s), 6.84 (2H, d, J=8.7 Hz), 7.03-7.08 (1H, m), 7.44 (2H, d, J=8.7 Hz), 7.54-7.57 (1H, m), 7.67-7.69 (1H, m), 9.62 (1H, s), 9.75 (1H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([CH3:22])[C:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)=[O:8].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1.C(OCC)(=O)C>[C:23]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([CH3:22])[C:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)=[O:8])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(COCCO)C(=O)c1ccc(Cc2cccnc2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCCOCC(C)C(=O)c1ccc(Cc2cccnc2)cc1

Procedure:
In 3 ml of pyridine was dissolved 2.0 g of 3-[p-[3-(2-hydroxyethyl)oxy-2-methylpropionyl]benzyl]pyridine, and 0.76 ml of acetic anhydride was added to the resulting solution with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 12 hours. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was dissolved in 16 ml of ethyl acetate. The resulting solution was washed with 5 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain crude oily 3-[p-[3-(2-acetoxyethyl)oxy-2-methylpropionyl]benzyl]pyridine. This was dissolved in 17 ml of ethanol.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[NH:22][N:23]=[CH:24][C:17]=12.CO>C(Cl)Cl.CO>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[NH:22][N:23]=[CH:24][C:17]=12)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCNc1ncnc2[nH]ncc12
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CO
Solvent: ClCCl
Product: OC(CNCCNc1ncnc2[nH]ncc12)COc1ccccc1
Reaction time: 5 h
Yield: 55 %

Procedure:
3.2 g. Phenyl glycidyl ether and 5.9 g. 4-(2-aminoethylamino)-pyrazolo[3,4-d]pyrimidine are stirred in 100 ml. methanol for 24 hours at ambient temperature and then for 5 hours at 80° C. Solid material (0.8 g.) is then filtered off with suction, the filtrate is evaporated and the yellowish oil obtained is dissolved in methylene chloride-methanol (9:1 v/v) and purified chromatographically in the manner described in Example 50. There is obtained 1.8 g. (26% of theory) of the desired product in the form of colorless crystals; m.p. 142°-144° C., after recrystallization from ethanol.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.CO.[OH-].[Na+].Cl>C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-[(trans-4-hydroxycyclohexyl)amino]quinazoline-7-carboxylate (3090 mg, 10.3 mmol) in THF (100 mL) was added MeOH (20 mL) followed by 2 M NaOH (20 mL, 40 mmol) and the mix stirred at R.T. for 3 hours. The solvents were stripped and the mix acidified with a stoichiometric amount of 1M HCl giving a yellow precipitate that was filtered off and washed with water and air dried to yield the title compound as a bright yellow solid, 2.7 g, 92%. 1H NMR (400 MHz, DMSO-D6) δ ppm 13.30 (1H, s) 9.17 (1H, s) 7.96 (1H, s) 7.85 (1H, d, J=8.34 Hz) 7.64 (1H, d, J=8.34 Hz) 7.48 (1H, s) 4.57 (1H, s) 3.79 (1H, s) 1.79-2.04 (4H, m) 1.17-1.43 (4H, m); MS (API−) for C15H17N3O3 m/z 286.1 (M−H)+.
Reaction SMILES: BrBr.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:16]#[N:17])[C:13]([NH2:15])=[S:14])=[CH:8][CH:7]=1)([O-:5])=[O:4].C(=O)([O-])O.[Na+]>ClC(Cl)C.ClCCCl>[NH2:15][C:13]1[S:14][C:10]2[CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=2[C:12]=1[C:16]#[N:17]
Reactant: N#CC(C(N)=S)c1ccc([N+](=O)[O-])cc1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: N#Cc1c(N)sc2cc([N+](=O)[O-])ccc12
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
A solution of 1.3 ml (25 mmol) of bromine in 10 ml of dichloroethane is added dropwise to a suspension of 5.53 g (25 mmol) of p-nitrophenylcyanothioacetamide and 4.2 g (50 mmol) of sodium hydrogencarbonate in 40 ml of 1,2-dichloroethane. The temperature is maintained at 20° C. by cooling with ice-water. This is followed by 30 minutes of stirring, filtering off with suction and washing with water. Drying in vacuo at 50° C. leaves 4.9 g of a brown powder=89% of theory.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:12]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Br:12][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[F:1]
Reactant: Nc1cccc(F)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 3-fluoro-2-nitroaniline (2.1 g, 13.4 mmol) in DMF (30 mL) at 0° C. was added a solution of N-bromosuccinimide (2.4 g, 13.4 mmol) in DMF (20 mL). The resulting solution was stirred at 0° C. for 30 minutes and then warmed to room temperature over 1 hour. The solution was diluted with EtOAc, washed with H2O and brine, dried over MgSO4, filtered and concentrated to give the title compound (3.1 g, 97%).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:31]=[CH:32][CH:33]=2)[C:22]([NH:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[O:23])=[CH:13][CH:12]=1)(=[NH:10])[NH2:9].[OH-].[Na+].C(O)(C(F)(F)F)=O>CO>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[C:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:31]=[CH:32][CH:33]=2)[C:22]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:15][CH:16]=1)(=[NH:9])[NH2:10]
Reactant: COC(=O)CCNC(=O)c1cccc(COc2ccc(C(=N)N)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N=C(N)c1ccc(OCc2cccc(C(=O)NCCC(=O)O)c2)cc1
Yield: 88.9 %

Procedure:
XX (0.21 mmol, 100 mg) was dissolved in 2 mL methanol and 2 mL 1N NaOH and after 1 hour the solution was acidified with TFA to pH 3. Purification on reversed phase HPLC gave 85 mg (88%) product. ESI (M+H)+ : Calc. 342.2; Found 342.2.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].C[OH:15]>O>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2](=[O:15])[C:3](=[O:12])[NH:4]2)=[CH:9][CH:8]=1
Reactant: CO
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Br
Solvent: O
Product: O=C1Nc2cc(Cl)ccc2C1=O
Yield: 88 %

Procedure:
3,3-Dibromo-6-chloro-1,3-dihydro-indol-2-one (21.34 g, 59.7 mmol) was suspended in a 4:1 (v:v) mixture of MeOH (172 mL): water (43 mL) and heated at reflux for 19 hr. The reaction was cooled in an ice bath and filtered. The red solid was washed once with cold CH3OH and dried to give the title compound as a red solid (10.49 g, 88% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (API-ES+) m/z 182/184 [M+H], 1 chlorine pattern observed.
Reaction SMILES: [C:1]([CH:4](/[CH:8]=[CH:9]\[F:10])[C:5](O)=[S:6])(=[O:3])[NH2:2].[NH2:11][C@H:12]1[CH2:16][O:15][N:14]([C:17]2([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:21][CH2:20][C:19](=[O:22])[O:18]2)[C:13]1=[O:39]>>[C:1]([CH:4](/[CH:8]=[CH:9]\[F:10])[C:5]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:17]2([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:21][CH2:20][C:19](=[O:22])[O:18]2)[C:13]1=[O:39])=[S:6])(=[O:3])[NH2:2]
Reactant: N[C@H]1CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)CCC(=O)O2)C1=O
Reactant: NC(=O)C(/C=C\F)C(O)=S
Product: NC(=O)C(/C=C\F)C(=S)N[C@H]1CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)CCC(=O)O2)C1=O

Procedure:
A procedure similar to Example 1 (a), using 179 mg of (Z)-2-carbamoyl-2-fluorovinylthioacetic acid and 356 mg of benzhydryl ester of a deacetyl compound of TAN-588, gave 358 mg of benzhydryl 2-{(4S)-4-[(Z)-2-carbamoyl-2-fluorovinylthioacetamido]-3-oxo-2-isoxazolidinyl}-5-oxo-2-tetrahydrofurancarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=2)=[CH:4][CH:3]=1
Reactant: Fc1cccc(CCl)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the acylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 3-fluorobenzyl chloride gave the title compound.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:9](=[O:10])[O:8][C:7]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[N:6]1)C.[C:21]([O:25][C:26](=[O:34])[NH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[C:21]([O:25][C:26](=[O:34])[NH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH:4]=[C:5]2[C:9](=[O:10])[O:8][C:7]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)=[N:6]2)[CH2:30][CH2:29]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC=C1N=C(c2cccc3ccccc23)OC1=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(C=C2N=C(c3cccc4ccccc34)OC2=O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-ethoxymethylene-2-naphthalen-1-yl-4H-oxazol-5-one (6.30 g, 23.7 mmol) in tetrahydrofuran, piperidin-4-yl-carbamic acid tert-butyl ester (4.70 g, 23.7 mmol) was added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure to yield [1-(2-naphthalen-1-yl-5-oxo-oxazol-4-ylidenemethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5]O.S(Cl)([Cl:15])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][Cl:15]
Reactant: COc1ccc(OC)c(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(OC)c(CCl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
In a nitrogen atmosphere, 2.00 g (11.9 mmol.) of 2,5-dimethoxybenzyl alcohol was dissolved in 10 ml of dichloromethane. The obtained solution was placed in an ice-bath, and to this was dropwise added a solution of 0.87 ml (12.0 mmol.) of thionyl chloride in 2 ml of dichloromethane. The mixture was then stirred at room temperature for 1.5 hour. The mixture was placed under reduced pressure at room temperature to distill off the solvent to give 2.22 g of the desired compound as a pale yellow oil.
Reaction SMILES: CN(C)C=O.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH2:17]([O:22][CH3:23])[CH2:18][CH2:19][C:20]#[CH:21]>[Cu]I.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.C(N(CC)CC)C>[CH3:23][O:22][CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: NS(=O)(=O)c1ccccc1I
Reactant: C#CCCCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCC#Cc1ccccc1S(N)(=O)=O
Reaction time: 22 h

Procedure:
135 ml of N,N-dimethylformamide and 22 ml of triethylamine are taken and 7.5 g of 2-iodobenzenesulfonamide, 2.6 g of pent-4-yn-1-yl-methyl ether as well as 0.067 g of copper(I) iodide and 0.144 g of bis(triphenylphosphine)palladium(II) dichloride are added. The reaction mixture is heated to 65° and stirred for 22 hours at that temperature under argon. After that time, the N,N-dimethylformamide is distilled off at 0.1 torr and 40°. The crude product is purified on 500 g of silica gel (Merck Si 60, 40-63 μm) with hexane/ethyl acetate=2/1 as eluant. The fractions containing the product are concentrated by evaporation at 15 torr and 40° to yield white crystalline 2-(5-methoxy-pent-1-yn-1-yl)-benzenesulfonamide, melting point: 59°-61°.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20]([C:22]2[C:23]([S:28][CH3:29])=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:14][CH2:13]1>ClCCl>[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20]([C:22]2[C:23]([S:28]([CH3:29])=[O:6])=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:13][CH2:14]1
Reactant: CSc1ncccc1C(=O)c1cnoc1C1CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncccc1C(=O)c1cnoc1C1CC1
Temperature: -20 °C

Procedure:
3-Chloroperoxybenzoic acid, an oxidant (2.85 g), was added to a stirred solution of 5-cyclopropyl-4-(2-methylsulphenylpyridin-3-oyl)isoxazole (236 g) in dichloromethane at -20° C. A further quantity of the oxidant (0.14 g) was added after 5 minutes. The reaction mixture was stirred at -20° C. until analysis (by thin layer chromatography) indicated reaction was complete. The mixture was filtered and the filtrate was washed successively with aqueous sodium bicarbonate solution and aqueous sodium metabisulphite solution, dried (anhydrous magnesium sulphate), filtered and evaporated. The crude product was suspended in refluxing acetonitrile. The suspension was cooled to room temperature and filtered. The product was dried to yield 5-cyclopropyl-4-(2-methylsulphinylpyridin-3-oyl)isoxazole (compound 7, 2.0 g) as colourless crystals, m.p.148°-152.4° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=4)=[C:22]([CH3:32])[CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-:36].[Na+].Cl>CC(C)=O>[C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]([N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13][N:14]4[C:5]([C:3]([OH:36])=[O:4])=[CH:6][CH:7]=[C:8]4[CH2:9]3)=[O:33])=[CH:21][C:22]=2[CH3:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1C1=CCCCC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
2,2,2-Trichloro-1-[10-(4-cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-ethanone of Step D (0.700 g, 1.33 mmol), was dissolved in acetone (8.9 mL) followed by addition of 2.5 N sodium hydroxide (1.60 mL, 3.99 mmol). The reaction was stirred at room temperature for 3 hours, and acidified with 2 N hydrochloric acid. The acidic mixture was extracted with diethyl ether and the organic phase extracted with 1 N sodium hydroxide. The combined basic extracts were acidified with 2 N hydrochloric acid, and extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was recrystallized from diethyl ether to afford 450 mg of the title compound as white crystals, 193° C. (dec.)
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[CH:8](OCC)=[CH2:9]>>[CH:8]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][OH:6])=[CH2:9]
Reactant: C=COCC
Reactant: OCCOCCO
Product: C=COCCOCCO
Reaction time: 10 h
Yield: 37.5 %

Procedure:
Diethylene glycol (85 g, 0.8 mol), ethyl vinyl ether (80 ml, 0.8 mol) and, as the catalyst, mercuric acetate Hg(CH3COO)2 are charged to a 3-neck flask of 250 ml, equipped with condenser and inlets for the reactants and an inert gas. The system is kept under refluxing conditions, at a temperature of 70°-80° C., for 10 hours. The product is recovered by extraction with methylene chloride and is separated from the corresponding divinyl ether by distillation. In that way, 40 g (0.3 mol) of diethylene glycol monovinyl ether is obtained, with a yield of 40%, and is added to a solution containing 40 ml of ethyl ether and 53 ml of pyridine. To the resulting mixture, kept at room temperature and under a flowing nitrogen stream, methacryloyl chloride (38.3 g, 0.37 mol) is added dropwise. The addition of the chloride causes the immediate precipitation of pyridinium hydrochloride. The reaction is discontinued when the disappearance of the monovinyl ether is observed. The product (A) is recovered from the reaction mixture via HPLC, using silica as the stationary phase and a mixture of 8:1 hexane:ethylacetate as the eluent. 42 g of 99%-pure product is obtained, which corresponds to a yield of 70% relatively to diethylene glycol monovinyl ether.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][NH:12][C:13]=2[NH:14]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:20][CH:21]=[CH2:22])[CH3:19].Cl>C(Cl)Cl.O1CCOCC1>[CH2:18]([O:20][CH:21]([N:12]1[C:13]([NH2:14])=[C:9]([C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=[N:11]1)[CH3:22])[CH3:19]
Reactant: C=COCC
Reactant: CC(=O)Nc1[nH]ncc1C#Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(C)n1ncc(C#Cc2ccccc2)c1N
Temperature: 75 °C
Yield: 80.3 %

Procedure:
A solution of N-(4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide (17.6 g, 78 mmol), ethoxyethene (11.2 mL, 117 mmol) and HCl in 1,4-dioxane (1 mL, 4 mmol) in CH2Cl2 (520 mL) was stirred at room temperature for 1 h and concentrated in vacuo. The residue was dissolved in ethanol (260 mL) and 25% aq. NaOH solution (260 mL) and the reaction mixture was heated to 75° C. for 4 h and cooled to room temperature. The ethanol was part concentrated in vacuo and the resulting solid collected by filtration, washed with water and minimum cold ethanol and dried in vacuo to provide the title compound as a solid (16 g).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:20]=[C:19]([CH:21]=[O:22])[CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[CH:10][CH:11]=2)[N:6]([CH3:23])[C:5]1=[O:24].[CH3:27][Mg]Br>C1COCC1.CO>[CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:20]=[C:19]([C@@H:21]([OH:22])[CH3:27])[CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[CH:10][CH:11]=2)[N:6]([CH3:23])[C:5]1=[O:24]
Reactant: C[Mg]Br
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(C=O)ccc3C#N)nc21
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](O)c1ccc(C#N)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask, 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-formylbenzonitrile (30-1) (70 mg, 0.2 mmol) was added under nitrogen, dissolved in THF (1 mL), and cooled to −78° C. 3M methylmagnesium bromide (0.08 ml, 0.24 mmol) was added slowly to the cooled solution and allowed to stir for 30 minutes. The reaction was warmed to room temperature for 30 minutes until complete conversion over starting material. The mixture was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-[(1S)-1-hydroxyethyl]benzonitrile (30-2). HRMS (M+H)+: observed=365.1976, calculated=365.1972.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([NH:9][C@@H:10]([C:23]([NH:25][C@H:26]([C:34]([N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH:21]=[O:22])[CH:13]=1)=[O:8])[C@@H:4]([CH3:6])[OH:5].C(N(CC)CC)C.[CH3:52][C:53](OC(C)=O)=[O:54]>C(Cl)Cl>[NH:2]([C:53]([CH3:52])=[O:54])[C@H:3]([C:7]([NH:9][C@@H:10]([C:23]([NH:25][C@H:26]([C:34]([N:36]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH3:37])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH:21]=[O:22])[CH:13]=1)=[O:8])[C@@H:4]([CH3:6])[OH:5]
Reactant: C[C@@H](O)[C@H](N)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H](C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1)[C@@H](C)O
Reaction time: 0.75 h
Yield: 83.1 %

Procedure:
To a solution of HCl.H-Thr-D-Trp(CHO)-Phe-NMeBzl (2.29 g) in methylene chloride (30 ml), were added triethylamine (747 mg) and Ac2O (377 mg) at -20° C. The reaction mixture was stirred for 45 minutes at the same temperature, and washed successively with water, diluted sodium hydrogencarbonate solution, water, 0.5N hydrochloric acid, and sodium chloride solution and dried over magnesium sulfate. After concentration, the residue was dissolved in 65% aqueous ethanol (45 ml) under heating, and the solution was left standing overnight at room temperature. The resulting needles were filtered, washed with 65% aqueous ethanol, and dried to give Ac-Thr-D-Trp(CHO)-Phe-NMeBzl (1.92 g).