Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Sn](Cl)Cl.[N:4]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[C@H:6]([NH:12][C:13]([C:15]1[O:16][C:17]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:18]=3[CH:19]=1)=[O:14])[CH2:5]2>CN(C=O)C.CO>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11]1)[C@H:6]([NH:12][C:13]([C:15]1[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:18]=3[CH:19]=1)=[O:14])[CH2:5]2
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ccc2oc(C(=O)N[C@@H]3CN4CCC3CC4)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.0 ml (4 mmol) of a 2 M tin(II) chloride solution in DMF are added to N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzofuran-2-carboxamide (135 mg, 0.32 mmol), and the mixture is stirred at RT for 18 h. The crude product is taken up in methanol and shaken together with acidic ion exchange resin (Dowex WX2-200) for about 20 min. The loaded ion exchanger is washed three times with in each case 30 ml of methanol, then with water/methanol 8:2, again with methanol, with dichloromethane and finally again with methanol. The product is eluted using methanol/triethylamine 95:5. The solvent is removed under reduced pressure using a rotary evaporator, and 20 ml of 1N aqueous sodium hydroxide solution are added to the crude mixture. The aqueous phase is extracted six times with in each case 20 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and the solvent is removed under reduced pressure using a rotary evaporator. 100.7 mg (82% of theory) of the title compound are isolated. The analytical data correspond to those of the enantiomeric compound from example 32.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14](OC)=[O:15])[N:9]=[CH:8]1.O.[OH-].[Na+]>O1CCCC1>[NH:9]1[C:10]([CH2:12][CH2:13][CH2:14][OH:15])=[CH:11][N:7]=[CH:8]1
Reactant: COC(=O)CCc1c[nH]cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1cnc[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 279.1 %

Procedure:
Add lithium aluminum hydride (1M in tetrahydrofuran; 17 mL; 2.0 equiv; 17.00 mmoles) dropwise over 5 minutes to a 0° C. solution of methyl 3-(1H-imidazol-4-yl)propanoate (2.2 g; 1.0 equiv; 8.52 mmoles) in tetrahydrofuran (85 mL). Warm the reaction mixture to ambient temperature and stir for 16 hours. Add water (0.65 mL), 15% sodium hydroxide (0.65 mL), and water (1.95 mL) sequentially, then stir for 30 minutes. Filter the resulting solid and rinse with acetone. Concentrate the filtrate to afford 3-(1H-imidazol-5-yl)propan-1-ol (3.0 g; 61%) as a white solid. To further purify the product, suspend a portion of 3-(1H-imidazol-4-yl)propan-1-ol (1.5 g) in water (50 mL) and stir at 100° C. for 2 hours. Filter the product mixture and concentrate the filtrate to afford pure 3-(1H-imidazol-5-yl)propan-1-ol (0.5 g) as an off white solid: MS (m/z): 127(M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[C:3]=12.[CH3:25][N:26](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:25]#[N:26])=[CH:19][CH:18]=3)[C:3]=12
Reactant: CN(C)C=O
Reactant: Cn1nc(-c2ccc(I)cc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cn1nc(-c2ccc(C#N)cc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 100 °C

Procedure:
A degassed mixture of 4-chloro-3-(4-iodophenyl)-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (Compound 43, Example 23) (70 mg, 0.16 mmol), Zn(CN)2 (18 mg, 0.094 mmol) and Pd(PPh3)4 (18 mg, 0.016 mmol) in DMF (1 mL) was heated at 100° C. for 40 min in a microwave. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried using a phase separating cartridge and concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, 10 to 20% ethyl acetate/isohexane), yielding Compound 24 as a solid (30 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.O[Li].O>O>[Cl:20][C:19]1[C:13]2[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)[NH:15][C:14]=2[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cnn(-c2nc3c(Cl)cccc3[nH]2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn(-c2nc3c(Cl)cccc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a mixture of 1-(4-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.180 g, 0.550 mmol), THF (3 mL), and water (1 mL), was added LiOH.H2O (95.0 mg, 2.20 mmol). The mixture was stirred 18 h at 23° C. The solvent was evaporated, water (3 mL) was added and the mixture acidified with aq. 1M HCl. The resulting white precipitate was filtered and dried to yield the titled compound (0.130 g, 90%). MS (ESI/CI): mass calcd. for C11H7ClN4O2, 262.0; m/z found, 263.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.64 (s, 1H), 12.97 (s, 1H), 8.90 (s, 1H), 8.30 (s, 1H), 7.48 (d, J=7.4 Hz, 1H), 7.32 (dd, J=7.8, 1.0 Hz, 1H), 7.25 (t, J=7.9 Hz, 1H).
Reaction SMILES: [N+:1]([N:4]1[CH2:11][CH2:10][CH2:9][C@H:5]1[C:6]([OH:8])=[O:7])([O-])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CCOCC>[N:1]1[O:7][C:6]([O-:8])=[C:5]2[CH2:9][CH2:10][CH2:11][N+:4]=12
Reactant: O=C(O)[C@@H]1CCCN1[N+](=O)[O-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOCC
Product: [O-]c1on[n+]2c1CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Nitroproline (17.0 g, 118 mmol) was suspended in ether (400 ml) and cooled in ice. Trifluoroacetic anhydride (16.5 ml, 120 mmol) was then added dropwise over 30 minutes and the mixture left to warm to room temperature whilst stirring over 16 hours. The mixture was evaporated in vacuo to an oil and purified by column chromatography on silica gel using an eluant of ethyl acetate to afford the title compound, 9.8 g.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[O:12][CH3:13].[Cl:14]C1C=CC(OC)=CC=1N>>[Cl:14][C:6]1[CH:7]=[CH:2][C:3]([O:12][CH3:13])=[CH:4][C:5]=1[S:8]([Cl:11])(=[O:10])=[O:9]
Reactant: COc1ccc(Cl)c(N)c1
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Product: COc1ccc(Cl)c(S(=O)(=O)Cl)c1

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 2-chloro-5-methoxy-phenylamine.
Reaction SMILES: C[O-].[Na+].[O:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[CH2:5]1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16]1>CN(C=O)C>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=[C:5]2[C:6](=[O:14])[NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:4]2)=[CH:16]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=C1COc2ccccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2OC1=Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium methoxide (0.65 g, 0.012 mol) was added in one portion to a mixture of 2H-1,4-benzoxazin-3(4H)-one (1.49 g, 0.01 mol) and indole-3-carboxaldehyde (2.32 g, 0.016 mol) in dry DMF (10 ml). The reaction mixture was refluxed for 24 h, then cooled at room temperature and poured into crushed ice and left overnight in the refrigerator. The precipitated solid was collected by filtration, washed with water and dried. The crude product was chromatographed on silica gel using (9:1) toluene:ethyl acetate.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CO>[CH2:4]([O:3][C:1]([NH:11][CH:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][Br:26])=[CH:18][CH:19]=1)[C:21]([OH:23])=[O:22])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: BrCCCCCBr
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC(Cc1ccc(OCCCCCBr)cc1)C(=O)O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
N-CBZ-L-tyrosine (2.06 g, 5.86 mmole) was treated with NaH (0.58 g, 12.08 mmole) and 1,5-dibromopentane (0.8 ml, 5.87 mmole) as described for 1-1 in Example 1. The crude product was dissolved in methanol and after stirring with silica gel for 0.5 hour, the solvent was removed. This was dry packed and eluted on a flash column with CHCl3 and then with 97:3:0.3 CHCl3 /CH3OH/HOAc to give pure 1-10.
Reaction SMILES: O[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].N1C=CC=CC=1.P(Br)(Br)[Br:18].Cl>CCOCC>[Br:18][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)CCCC#CCO
Reactant: BrP(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(O)CCCC#CCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-hydroxy-5-heptynoic acid (88.2 g), described in Example 78, in anhydrous ether (300 ml) and pyridine (12 ml) is added dropwise phosphorus tribromide (67.5 g) at 10° C. The solution is stirred at room temperature for 30 min. then cooled to 5° C and 10% HCl (120 ml) is added slowly. The organic layer is washed with water and 10% sodium carbonate, dried (Na2SO4) and concentrated. The residue is distilled under reduced pressure to give 7-bromo-5-heptynoic acid, b.p. 146° C, 0.8 mm.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: Oc1cccc2ccc(Cl)nc12
Solvent: O
Product: Oc1cccc2ccc(N3CCOCC3)nc12
Yield: 80 %

Procedure:
To a stirred mixture of 2-chloroquinolin-8-ol (1.7 g crude, 9.5 mmol) was added morpholine (5 mL). The mixture was heated at reflux for 16 hours. After cooling, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was used directly for the next step. (1.6 g, Yield 80%). LCMS (m/z): 231.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1.[OH:29][C:30]1[CH:40]=[CH:39][C:33]([C:34]([NH:36][O:37][CH3:38])=[O:35])=[CH:32][C:31]=1[O:41][CH3:42].C(=O)([O-])[O-].[K+].[K+]>>[CH3:42][O:41][C:31]1[CH:32]=[C:33]([CH:39]=[CH:40][C:30]=1[O:29][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1)[C:34]([NH:36][O:37][CH3:38])=[O:35]
Reactant: NS(=O)(=O)c1cccc(-c2c(Cl)nc(C(F)(F)F)nc2-c2ccc(F)cc2)c1
Reactant: CONC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CONC(=O)c1ccc(Oc2nc(C(F)(F)F)nc(-c3ccc(F)cc3)c2-c2cccc(S(N)(=O)=O)c2)c(OC)c1

Procedure:
A suspension of 3-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide (0.15 g, 0.35 mmol), 4-hydroxy-N,3-dimethoxybenzamide (0.102 g, 0.52 mmol) and potassium carbonate (0.52 mmol) in acetonitrle (3 ml) were heated to relfux (65° C.) for 2 hours. Subsequently the reaction mixture was poured onto ice-cold water, extracted with dichloromethane (50 ml) and washed with brine. Evaporation of the organic layer furnished a crude material, which was purified by column chromatography; elution with 2% MeOH in dichloromethane furnished the required compound. 1H-NMR (DMSO-d6) δ: 3.73 (s, 3H), 3.79 (s, 3H), 7.16-7.20 (m, 2H), 7.37 (d, 1H), 7.41-7.45 (m, 5H), 7.53 (s, 1H), 7.62-7.63 (d, 2H), 7.85 (d, 1H), 7.89 (s, 1H). 11.9 (s, 1H); MS m/z: 593 (M++1).
Reaction SMILES: Br[C:2]1[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]2[CH:5]=[C:6]([Cl:16])[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]=2[C:10]=1[CH3:11].[CH3:20]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>O1CCOCC1.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>[Cl:16][C:6]1[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:10]([CH3:11])=[C:2]([CH3:20])[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]=2[CH:5]=1
Reactant: COC(=O)c1cc(Cl)cc2c1c(C)c(Br)n2C(C)C
Reactant: CB1OB(C)OB(C)O1
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+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc2c1c(C)c(C)n2C(C)C
Temperature: 110 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a stirred solution of methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.50 g, 1.451 mmol), Trimethylboroxine (0.30 mL, 2.146 mmol) and potassium carbonate (0.31 g, 2.243 mmol) in 1,4-Dioxane (20 mL) under N2 was added palladium tetrakis (0.18 g, 0.156 mmol). The reaction was heated to 110° C. and stirred for 18 hr. After 3 hr an additional 100 uL Trimethylboroxine was added. The reaction was concentrated under vacuum, taken up in EtOAc, washed with water, dried (MgSO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-60 g, 0 to 10% EtOAc in hexanes) gave the product methyl 6-chloro-1-isopropyl-2,3-dimethyl-1H-indole-4-carboxylate (0.33 g, 1.180 mmol, 81% yield) as a clear thick oil. 1H NMR (400 MHz, DMSO-d6) δ=7.80 (d, J=2.0 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 4.81 (dt, J=6.9, 13.9 Hz, 1H), 3.87 (s, 3H), 2.39 (s, 3H), 2.13 (s, 3H), 1.51 (d, J=7.1 Hz, 6H) MS (ES)+m/e 280.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(Cc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 3.36 g of sodium hydride (in mineral oil) in 50 ml of dimethylformamide is added dropwise at room temperature a solution of 15 g bis-(p-hydroxyphenyl)-methane in 50 ml dimethylformamide. The resulting solution is stirred at room temperature for one hour. Ten grams of benzyl chloride is added dropwise and the stirring is continued at room temperature overnight. After evaporation of the solvent under reduced pressure, the residue is treated with 100 ml of water and extracted twice with diethyl ether. The combined ether extracts are combined, dried over anhydrous magnesium sulfate, evaporated to dryness, and the resulting oil dissolved in hot ethanol. Bis-p-(benzyloxy)phenyl-methane (m.p. 109.5°-110°C) crystallizes upon cooling and is collected by filtration. The mother liquors are evaporated to dryness and the crystalline mono-addition product is obtained by chromatography on silica gel with chloroform. After separation, the mono-benzyl ether is recrystallized from isopropyl ether, m.p. 95°-96°C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH:24][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Reactant: CN(C)CCN
Product: CN(C)CCNc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12

Procedure:
7-Chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (1 g) and N,N-dimethylethylenediamine (30 ml) were heated in a sealed tube at 180° C. for 10 days. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated potassium carbonate solution. The organic layer was separated, dried (Na2SO4) and the solvent was removed under vacuum. The residue was dissolved in HCl, washed with diethyl ether (2×), then basified with sodium hydroxide, extracted into ethyl acetate, dried (MgSO4), and concentrated in vacuo, to give 0.248 g of the title compound; mp 230° C. (ethyl acetate); Found: C, 63.76; H, 5.64; N, 11.75.C19H2O ClN3O.0.9H2O requires C, 63.37; H, 6.14; N, 11.76%. δ (360 MHz, DMSO-d6) 1.94 (6H, s, (CH3)2N), 2.17 (2H, m, NCH2CH2N), 2.69 (2H, m, NCH2CH2N), 5.82 (1H, br s, NH), 7.17-7.95 (8H, m, aromatics), 11.23 (1H, br s, NH); m/z (CI+) 341 (M+).
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](#[N:17])[CH:15]=[CH2:16].C[O-].[Na+]>>[CH2:1]([S:13][CH2:16][CH2:15][C:14]#[N:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C=CC#N
Reactant: CCCCCCCCCCCCS
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCSCCC#N

Procedure:
β-n-Dodecylmercaptopropionitrile was prepared according to the procedure of Example 1 using 1-dodecanethiol (24.75 g; 0.12 moles), acrylonitrile (6.4 g; 0.21 moles) and sodium methoxide (0.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:29][CH:28]=2)[CH2:25][CH2:26]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1
Product: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH2:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=4[F:36])=[O:27])[CH:24]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[F:36][C:30]1[C:31]([F:35])=[CH:32][CH:33]=[CH:34][C:29]=1[NH:28][C:26](=[O:27])[CH2:25][N:23]1[CH:24]=[C:20]([NH:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=3)[N:16]=[CH:15][N:14]=2)[CH:21]=[N:22]1
Reactant: O=C(Cn1cc(Nc2ncnc3cc(OCc4ccccc4)ccc23)cn1)Nc1cccc(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cn1cc(Nc2ncnc3cc(O)ccc23)cn1)Nc1cccc(F)c1F
Yield: 99.8 %

Procedure:
2-(4-{[7-(benzyloxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(2,3-difluorophenyl)acetamide (836 mg, 1.60 mmol) was dissolved in trifluoroacetic acid (8 ml) and heated under reflux for 2.5 hours. The solution was concentrated and the residual oil was dissolved in methanol and neutralised with an aqueous solution of sodium bicarbonate. Water was added to the mixture and the solid recovered by filtration and dried in vacuo to yield N-(2,3-difluorophenyl)-2-{4-[(7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (633 mg, 100% yield):
Reaction SMILES: [NH2:1][C@@H:2]([CH2:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=1)[C@@H:3]([C@H:5]1[CH2:9][C@H:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][N:6]1C(C1C=CC=CC=1)C1C=CC=CC=1)[OH:4].[C:39]([NH:42][C@:43]1([C@@H:92]([CH2:94][CH3:95])[CH3:93])[CH2:47][CH2:46][N:45]([C@@H:48]([CH2:83][CH2:84][C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[C:49](N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2CCCCN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=[O:50])[C:44]1=[O:91])(=[O:41])[CH3:40].[Li+].[OH-].CO.C(Cl)(Cl)Cl>CCO.O>[C:39]([NH:42][C@:43]1([C@@H:92]([CH2:94][CH3:95])[CH3:93])[CH2:47][CH2:46][N:45]([C@@H:48]([CH2:83][CH2:84][C:85]2[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=2)[C:49]([NH:1][C@@H:2]([CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)[C@H:3]([OH:4])[C@H:5]2[CH2:9][C@H:8]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:7][NH:6]2)=[O:50])[C:44]1=[O:91])(=[O:41])[CH3:40]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@H](Oc2ccccc2)CN1C(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](Oc3ccccc3)CN2)C1=O
Temperature: 25 °C
Yield: 73 %

Procedure:
Step 9 (B): (1S,2S)-2-amino-1-((2R,4S)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4S)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)oxazolidin-2-one (Step 9 (A), 57 mg, 0.11 mmol) in EtOH (5 mL) was added a solution of LiOH (53 mg, 2.2 mmol) in H2O (1.5 mL). This reaction mixture was stirred at reflux for 4 h. After cooling down to rt, the mixture was concentrated to remove EtOH and H2O was added followed by 1N HCl solution and pH 7 buffer. The mixture was extracted with ethyl acetate and the organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 0-10% MeOH/chloroform) gave 41.1 mg (73% yield) of the title compound: 1H NMR (CDCl3, 300 MHz) δ 2.05-2.12 (1H, m), 2.21-2.30 (1H, m), 2.39 (1H, m), 2.62-2.72 (2H, m), 2.90-2.99 (2H, m), 3.39 (1H, dd, J=3, 12 Hz), 3.69 (1H, m), 4.80 (1H, m), 5.07 (1H, s), 6.65-6.68 (3H, m), 6.82 (2H, m), 6.93 (1H, m), 7.14 (1H, m), 7.20-7.31 (7H, m), 7.35-7.38 (4H, m). HPLC retention time: 1.65 min (method C). MS (ESI) (M+H)+ 515.35.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(=O)O)cc1F
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 g of 3-fluoro-4-methyl-benzoic acid are initially introduced into 100 ml of concentrated sulphuric acid, and a mixture consisting of 26 g of 98% strength nitric acid and 40 g of concentrated sulphuric acid is added dropwise at 20°-25°, while cooling with ice. The mixture is subsequently stirred at room temperature for 1 hour. The batch is then poured onto ice-water and the crystals are filtered off with suction and washed thoroughly with water. After drying and recrystallization from toluene, 48 g (74.3% of theory) of 2-nitro-4-methyl-5-fluorobenzoic acid of melting point m.p.: 163°-5° C. are obtained.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32])[CH2:4][NH:5][C:6](=[O:24])[CH2:7][N:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[N:9]1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[Cl:23][C:20]1[S:19][C:18]([C:10]2[N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:12](=[O:13])[N:8]([CH2:7][C:6]([NH:5][CH2:4][CH:3]([NH:2][S:36]([CH3:35])(=[O:38])=[O:37])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:32])([F:33])[F:34])=[O:24])[N:9]=2)=[CH:22][CH:21]=1
Reactant: COCCn1c(-c2ccc(Cl)s2)nn(CC(=O)NCC(N)c2ccccc2C(F)(F)F)c1=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COCCn1c(-c2ccc(Cl)s2)nn(CC(=O)NCC(NS(C)(=O)=O)c2ccccc2C(F)(F)F)c1=O

Procedure:
Analogously to the procedure of Example 68, 29 mg (46 μmol) of the compound of Example 60A were reacted with methanesulphonyl chloride. This gave 25 mg (92% of theory) of the title compound.