Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14].[I:18]I>C1CCCCC1.C1COCC1>[CH2:13]([O:12][C:11](=[O:15])[NH:10][C:5]1[C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:9][CH:8]=[CH:7][C:6]=1[I:18])[CH3:14]
Reactant: CCOC(=O)Nc1ccccc1OC(F)(F)F
Reactant: II
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCOC(=O)Nc1c(I)cccc1OC(F)(F)F
Reaction time: 1 h
Yield: 73 %

Procedure:
A 1.4 M solution of sec-buthyllithium in cyclohexane (3.0 mL) was added drop-wise to a solution of ethyl N-[2-(trifluoromethoxy)phenyl]carbamate (0.5000 g, 0.002006 mol) in THF (9 mL) at −70° C. After stirring for 1 hour a solution of iodine (0.51 g, 0.002 mol) in THF (1.0 mL) was added drop-wise at −70° C. Stirring was continued for another 1 hour then the mixture was quenched with saturated ammonium chloride solution. Water (50 mL) was added and the mixture extracted with diethyl ether (3×40 mL). The combined organic phases was washed with 40% sodium meta-bisulfite solution, water and brine, then dried over Na2SO4 and the solvent removed in vacuo to give the desired product in a 73% yield. 1H NMR (400 MHz, CDCl3): δ 1.29-1.36 (m, 3H), 4.21-4.28 (m, 2H), 6.21 (br, 1H), 7.05 (t, J=8.0 Hz, 1H), 7.30 (m, 1H) and 7.80 (dd, J=6.8, 1.2 Hz, 1H). MS (ES+): m/z 375.78 [MH+].
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH2:18]([O:20][C:21](=[O:27])[C@H:22]([CH:24]([CH3:26])[CH3:25])[NH2:23])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:27])[C@@H:22]([NH:23][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH:24]([CH3:26])[CH3:25])[CH3:19]
Reactant: CCOC(=O)[C@@H](N)C(C)C
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CCOC(=O)[C@@H](NC(=O)c1ccc(N2CCC(=O)CC2)cc1)C(C)C

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and L-valine ethyl ester hydrochloride according to the procedure of Example 154 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 0.93 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H), 2.10-2.30 (m, 1H), 2.43 (t, J=6.0 Hz, 4H), 3.72 (t, J=6.0 Hz, 4H), 4.00-4.30 (m, 4H), 4.46 (t, J=5.1 Hz, 1H), 7.05 (d, J=8.9 Hz, 2H), 7.82 (d, J=8.9 Hz, 2H), 8.21 (d, J=7.9 Hz, 1H); MS (ES) m/z: 347.3 (MH+); HRMS Calcd. for C19H26N2O4 (M+): 346.1892. Found: 346.1896.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:15][C:16]([NH:18][C@H:19]([C:31]([C@@H:33]1[C@H:36](OC(=O)C)[N:35]([NH2:41])[C:34]1=[O:42])=[O:32])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1COCC1>CC(C)=O.[OH-].[Na+]>[CH2:8]([O:15][C:16]([NH:18][C@H:19]([C:31]([C@@H:33]1[C@H:36]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:35]([NH2:41])[C:34]1=[O:42])=[O:32])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)O[C@H]1[C@@H](C(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)OCc2ccccc2)C(=O)N1N
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: NN1C(=O)[C@H](C(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)OCc2ccccc2)[C@@H]1Oc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
To a solution of phenol (30 mg, 0.32 mmol) in acetone (2 ml) and 1 N NaOH (0.25 ml), (3S,4S)-3{N-benzyloxycarbonyl-β-(2-naphthyl)-L-alanyl}-amino-4-acetoxy-azetidin-2-one (95 mg, 0.2 mmol) in acetone (1 ml) and THF (2 ml) was added at 5° C. The mixture was stirred at 5° C. for 1 hr and then at room temperature for 1 hr. After removal of solvent, the residue was dissolved in ethyl acetate, washed with water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (1:2) as eluent and 45 mg of (3S,4S)-3-{N-benzyloxycarbonyl-β-(2-naphthyl)-L-alanyl}-amino-4-phenoxy-azetidin-2-one was obtained.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][OH:16].N1C=CN=C1>CN(C=O)C.O>[CH:1]([Si:4]([O:16][CH2:15][C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=1[Br:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: OCc1ccccc1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCc1ccccc1Br)(C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Triisopropylsilyl chloride (8.0 ml, 46.0 mmol) was added dropwise to a solution of 2-bromobenzyl alcohol (7.0 g, 39.6 mmol) and imidazole (5.1 g, 75.0 mmol) in DMF (25 ml) and the resulting solution stirred at 20° C for 18 hours. The reaction mixture was diluted with water (400 ml) and extracted with ethyl acetate (3×75 ml). The combined organic extracts was washed with saturated brine (1×75 ml), dried (MgSO4) and concentrated to yield the title compound as a clear oil (10.2 g, 78%). 1H NMR (250 MHz, CDCl3) δ 1.05-1.24 (21 H, m), 4.82 (2 H, s), 7.11 (1 H, dt, J=7.5, 1.2), 7.34 (1 H, t, J=7.6), 7.48 (1 H, dd, J=7.9, 1.1), 7.63 (1 H, d, J=6.7).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CO>C(Cl)Cl>[N:19]1([CH2:18][CH2:17][CH2:16][N:11]2[C:12](=[O:15])[CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(CCCN2CCCCC2)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C1CCNCCN1CCCN1CCCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
A solution of 7.3 g (21.50 mmol) of 5-oxo-4-(3-piperidin-1-yl-propyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester was in 140 ml CH2Cl2, cooled to 0° C. and treated with 54 ml (215 mmol) of HCl solution (4 M dioxane), then warmed to RT. After 3 h, 40 ml of MeOH were added to dissolve the precipitation and stirring was continued over night. The solution was evaporated, dissolved in aq. sat. NaHCO3. solution, the water evaporated and the solid extracted with in CH2Cl2:MeOH 9:1. Concentration afforded the title compound 5.0 g (97%) as yellow oil. MS: 240.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([F:22])[CH:28]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4cccc(F)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-fluorophenylboronic acid (120 mg, 0.86 mmol) the subtitle compound was obtained, (103 mg, 49%). 1H NMR (DMSO) δ 8.59(d, 1H), 8.40(dd, 1H), 8.08(d, 1H), 7.82(d, 1H), 7.72(dd, 1H), 7.52(m, 4H), 7.17(dt, 1H), 4.02(s, 3H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.O[CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1>[NH:17]1[CH:18]=[C:14]([CH2:13][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[N:15]=[CH:16]1
Reactant: OCc1c[nH]cn1
Reactant: c1ccc2c(c1)CCCN2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc2c(c1)CCCN2Cc1c[nH]cn1
Temperature: 25 °C

Procedure:
A mixture of 1,2,3,4-tetrahydro-quinoline (Intermediate F1) (Commercially available from Aldrich) (1.62 mL, 12.6 mmol) and 4-hydroxymethyl-imidazole hydrochloride salt (commercially available from Aldrich) (Intermediate F2) (0.70 g, 5.1 mmol) and sodium carbonate (1.6 g, 15.1 mmol) in water (20 mL) and dioxane (10 mL) were heated at reflux for 24 h. The mixture was cooled to rt and extracted with ethyl acetate. The organic solution was dried over MgSO4, filtered and freed of solvent. The resultant oil was purified by chromatography on silica gel with 5% NH3-MeOH: dichloromethane to give 1-(1H-imidazol-4-ylmethyl)-1,2,3,4-tetrahydro-quinoline (Intermediate F3) as a solid, 0.54 g (50%).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:5]=1.S(Cl)([Cl:18])(=O)=O>C(Cl)Cl>[Cl:18][C:5]1[C:6]([C:10]([O:12][CH3:13])=[O:11])=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:14]
Reactant: COC(=O)c1cc(OC(F)F)n(C)n1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1nn(C)c(OC(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2.1 g (10 mmol) 5-Difluoromethoxy-3-methoxycarbonyl-1-methylpyrazole, dissolved in 30 ml methylene chloride, was treated with 1.35 g (10 mmol) sulfuryl chloride and the mixture stirred at room temperature for 10 minutes. It was then concentrated and the residue recrystallised from diisopropyl ether/ethyl acetate.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][C:5](F)=[CH:6][CH:7]=1.[CH3:18][O-:19].[Na+]>CO>[F:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][C:5]([O:19][CH3:18])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: CC1(CNc2nc(F)ccc2F)CCOCC1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(NCC2(C)CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.38 h

Procedure:
To a solution of 3,6-difluoro-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (1.4 g, 5.78 mmol) in MeOH (14 mL) was added sodium methoxide (25 wt. % in MeOH, 7 mL, 30.8 mmol). The mixture was heated in a steel bomb at 135° C. for 3 days. The mixture was cooled to ambient temperature and concentrated in vacuo. The resulting residue was taken up in water (200 mL), and the resulting precipitate was filtered off and rinsed with water. The solid was dissolved in DCM. The organic solution was washed with brine, dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 80 g, 20 min, EtOAc/heptane=0/100 for 2 min, then EtOAc/heptane=5/95 to 25/75 over 23 min, EtOAc/heptane=25/75] providing 3-fluoro-6-methoxy-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as an off-white solid. Yield: 1.22 g. LCMS (m/z): 255.1 [M+H]+; Retention time=0.89 min.
Reaction SMILES: [Na].O=[C:3]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][CH:5]=O.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[NH:21][C:22]([NH2:24])=[NH:23].[OH-].[K+]>C(O)CCC.C(O)(=O)C>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[NH:21][C:22]1[N:24]=[C:3]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:23]=1
Reactant: Cc1ccc(N)cc1NC(=N)N
Reactant: O=CCC(=O)c1cccnc1
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCCCO
Product: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C

Procedure:
Under inert atmosphere, 16 g sodium salt of β-oxo-3-pyridinepropanal, with HPLC purity of 99% (A %) and 25% salt content (residue by calcination), and 11.7 g (2-methyl-5-aminophenyl)guanidine in 115 mL n-butanol is suspended. 9 mL acetic acid is added, and the mixture is stirred at room temperature for an hour. 6 g potassium hydroxide is added portionwise, and the mixture is refluxed for 18 hours, removing the water with a Dean Stark apparatus. Once completed the conversion, the suspension is cooled and the organic layer is washed with water. The organic layer is concentrated to a small volume, and toluene is added. The precipitate is filtrated, yielding, upon drying, 15.5 g of product with HPLC purity of 99.2% (A %), identified through LC-MS and 1H-NMR.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8](Br)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([C:22]#[C:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Product: CCOC(=O)c1c(C)nc(C#Cc2ccc(Cl)cc2)n1C

Procedure:
The title compound, MS: m/e=303.0 (M+H+) was prepared in accordance with the general method of example 1b from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and 1-chloro-4-ethynylbenzene.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)#[N:15].N1C=CC=CC=1>ClCCl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:22][C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: N#Cc1ccc(S)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)Sc2ccc(C#N)cc2)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (3.33 g) in dry dichloromethane (20 ml) was added over 10 minutes to a cool (5° C.), stirred solution of 4-cyanothiophenol (2.06 g), pyridine (1.45 ml) and 4-N,N-dimethylaminopyridine (25 mg) in dry dichloromethane (30 ml). The stirred solution was allowed to reach room temperature overnight and the organic solution was washed successively with aqueous 2M hydrochloric acid, a saturated sodium bicarbonate solution and water. Evaporation of the extracts, which had been dried over magnesium sulphate, afforded the desired thioester (4.53 g).
Reaction SMILES: [CH2:1]([NH:8][NH:9][C:10]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=1[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.CCOCC>[CH2:1]([N:8]1[C:12](=[O:13])[C:11]2[C:10](=[CH:18][CH:17]=[C:16]([Cl:19])[CH:15]=2)[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccc1NNCc1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=c1c2cc(Cl)ccc2[nH]n1Cc1ccccc1
Yield: 68.5 %

Procedure:
A suspension of 2-(2-benzylhydrazino)-5-chlorobenzoic acid (2.5 g) in acetic acid (20 ml) was heated under reflux for 30 minutes. The solution was then cooled and diluted with ether. The solid which formed was recrystallised from ethanol to give 1,2-dihydro-2-benzyl-5-chloro-3H-indazol-3-one as a solid (1.6 g), m.p. 215-225° C. (dec.).
Reaction SMILES: [NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([CH2:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])[CH3:3].Cl.[H][H]>>[NH2:1][CH:2]([CH2:4][CH2:5][CH2:6][C:7]([CH:10]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH:12]([CH2:17][CH3:18])[CH2:11]1)([CH3:8])[CH3:9])[CH3:3]
Reactant: [H][H]
Reactant: CCc1cc(C(C)(C)CCCC(C)N)ccc1N
Agent: Cl
Product: CCC1CC(C(C)(C)CCCC(C)N)CCC1N

Procedure:
10.0 Parts of 2-amino-6-(4-amino-3-ethylphenyl)-6-methylheptane in 120 parts of 1N aqueous hydrochloric acid were shaken with hydrogen at room temperature and atmospheric pressure with 1.0 parts Nishimura catalyst. After 46% of theory hydrogen had been taken up in 18 hours a further 1.0 parts of catalyst was added and 96% of theory hydrogen uptake was reached in the next 15 hours. The hydrogenation which ceased at 110% theory during the next 24 hours following a final 1.0 part catalyst addition, was worked up according to Example 1, and gave on distillation 8.8 parts of 2-amino-6-(4-amino-3-ethylcyclohexyl)-6-methylheptane b12 176°-80° with the following percentage composition by weight.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].CN(C)C=O>CO>[CH3:17][N:18]([CH:20]=[CH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:19]
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(C=CN(C)C)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
Into a reaction flask were introduced 89.7 g of methyl 4-methyl-3-nitrobenzoate, 82.1 g of dimethylformamide dimethyl acetal and 200 ml of dimethylformamide (DMF), and the content of the flask was stirred at 120° C. for 6 hours. DMF was distilled off to obtain a red-violet colored solid product. Then, 300 ml of methanol was poured into the flask to wash the crystalline matter, and filtered. Thus, 104.8 g (yield 91%) of methyl 4-dimethylaminovinyl-3-nitrobenzoate was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7](Cl)(=[O:9])=[O:8].[NH:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[S:7]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)(=[O:9])=[O:8]
Reactant: c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1sccc1Br
Product: O=S(=O)(c1sccc1Br)n1cccc1

Procedure:
N-(3-bromothiophene-2-sulfonyl)pyrrole was prepared in the same manner as described in Example 33A by reacting 3-bromothiophene-2-sulfonylchloride with pyrrole (for 16 hr.). N-(3-bromothiophene-2-sulfonyl)pyrrole was obtained in 54% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[C@H:31]1([NH2:38])[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[NH2:37].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:37][C@H:32]4[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]4[NH2:38])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: N[C@H]1CCCC[C@@H]1N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC[C@@H]4N)n3)c3cc(Cl)cnc32)cc1

Procedure:
A solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 23a, (0.50 g, 1.08 mmol) in THF (4 mL) was treated with (1S,2S)-cyclohexane-1,2-diamine (0.27 g, 2.37 mmol) and iPr2NEt (2.15 mmol) at 120° C. for 10 minutes. The mixture was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-20% MeOH—CH2Cl2) to provide the desired intermediate as a white solid (410 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1.[CH:19](OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:15][C:11]1[CH:10]=[C:9]([N:8]2[C:7]3[CH:6]=[CH:5][C:4]([C:16](=[O:18])[CH3:17])=[CH:3][C:2]=3[N:1]=[CH:19]2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(=O)c1ccc(Nc2cccc(Br)c2)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1

Procedure:
This was prepared from 1-[3-amino-4-(3-bromo-phenylamino)-phenyl]-ethanone (86.5 g, 0.28 mol) by treatment with triethyl orthoformate in THF in the presence of p-toluenesulfonic acid as described in Example 1.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:27][CH:28]([CH3:31])[CH2:29][NH2:30]>C(#N)C>[CH3:27][CH:28]([CH3:31])[CH2:29][NH:30][CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][CH:19]=2)[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CC(C)CN
Solvent: CC#N
Product: CC(C)CNCC1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 25: [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0504 mmol), 2-methylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 297 (M+, 6), 254 (33), 130 (7), 87 (7), 86 (bp), 57 (9).
Reaction SMILES: N#N.[F:3][C:4]([F:18])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14](Cl)=[O:15])[N:13]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CC(C)=O.O>[F:3][C:4]([F:18])([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14]([N:19]=[N+:20]=[N-:21])=[O:15])[N:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(F)(F)CCCCc1nc(C(=O)Cl)co1
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(F)(F)CCCCc1nc(C(=O)N=[N+]=[N-])co1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of this crude 2-(5,5-difluoro-hexyl)-oxazole-4-carbonyl chloride was dissolved in dry acetone (12.0 mL). The solution was cooled to 0° C. and a solution of sodium azide (196 mg, 2.98 mmol) in H2O (1.4 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 45 min. The mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a brown solid. LC-MS-conditions 02: tR=0.98 min, [M+H]+=259.09.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([O:8][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:7]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: BrCC1CC1
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CC3)n(CC3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and bromomethyl-cyclopropane (7051-34-5). Off-white powder (35%). MS (Turbo Spray): m/z=431.0 (M+H).
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[NH2:13][C:14]([CH3:25])([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1)[CH3:15]>C(O)C>[CH3:25][C:14]([NH:13][CH2:12][C@@H:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[N:2][N:1]=2)[CH:9]=1)[OH:11])([CH3:15])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1
Reactant: CC(C)(N)CCc1cccc(O)c1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: CC(C)(CCc1cccc(O)c1)NC[C@H](O)c1ccc2nnnn2c1
Yield: 36.9 %

Procedure:
A solution of 194 mg (1.21 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane and 195 mg of 2-amino-2-methyl-4-(3-hydroxyphenyl)butane in 25 ml of absolute ethanol was heated at reflux for 6.5 hours. The reaction mixture was concentrated and the residue chromatographed on silica gel (4:1:2:1 ethyl acetate:n-propanol:water:ammonium hydroxide) to give 137 mg of product.