Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:34])[NH:16][C:17](=[O:33])[N:18]([CH2:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=3[F:32])[C:19]=2[CH3:20])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.ClCCl.[Pd]>[F:32][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([F:31])([F:30])[F:29])[C:22]=1[CH2:21][N:18]1[C:19]([CH3:20])=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15](=[O:34])[NH:16][C:17]1=[O:33]
Reactant: [H][H]
Reactant: Cc1c(N2CCN(Cc3ccccc3)CC2)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(N2CCNCC2)c(=O)[nH]c(=O)n1Cc1c(F)cccc1C(F)(F)F
Yield: 77.7 %

Procedure:
To a solution of 5-(4-benzyl-piperazin-1-yl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione (1.48 g, 3.11 mmol) in 10 mL of methanol/dichloromethane (1/1) was added 10% palladium/carbon (280 mg), after which the solution was stirred at room temperature for 5 hrs in a hydrogen atmosphere. Following the removal of palladium/carbon therefrom by filtration through cellite, the solution was concentrated. The residue was purified using amine silica gel chromatography (eluent: dichloromethane/methanol, 30/1→10/1) and dried in a vacuum to afford 934 mg of the compound as a white solid. (yield 79%). 1H NMR (300 MHz, CDCl3) δ 2.32 (3H, s), 2.52 (2H, m), 2.83 (2H, m), 2.96 (2H, m), 3.43 (2H, m), 5.37 (2H, s), 7.22 (1H, d), 7.40 (1H, dd), 7.54 (1H, d)
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].OS(O)(=O)=O>N1C=CC=CC=1>[Si:28]([O:22][CH2:21][CH:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[OH:20])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CCCCCCCCCCCCCCCCOCC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Compound 2a (2.297 g, 7.26 mmol) was dissolved in anhydrous pyridine (20 mL) at RT under argon. Imidazole (1.02 g, 14.52 mmol) in anhydrous pyridine (10 mL) was then added followed by tert-butyl dimethylsilyl chloride (TBDMS-Cl, 2.25 g, 14.52 mmol) in anhydrous pyridine (20 mL). The reaction mixture was stirred at RT for 72 hours, poured into 0.5 M H2SO4 (150 mL) and extracted with diethyl ether (100 mL, 3×). The extract was washed successively with saturated aqueous NaHCO3 (100 mL) and water (100 mL), dried over anhydrous Na2SO4 and the solvent removed under reduced pressure to obtain 3a, an oily material which was dried in a vacuum dessicator for 2 days (3.164 g, 100% yield). 1H NMR (in CDCl3): δ in ppm 0.83-0.89 (15H, m), 1.22 (29H, m), 1.52-1.53 (2H, m), 2.60 (1H, s, D2O exchangeable), 3.40-3.42 (4H, m), 3.59-3.61 (2H, m), 3.64 (1H, m); 13C NMR (in CDCl3): δ in ppm 14.3, 18.2, 18.5, 22.9, 25.8, 26.0, 26.1, 26.3, 29.6, 29.8, 29.9, 32.1, 33.0, 64.2, 70.8, 71.6, 71.9.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[C:29]([CH3:30])=[CH:28][S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]3[C:29]([CH3:30])=[CH:28][S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)csc3n2)cc1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: COC(=O)c1ccc(-c2nc(NCc3cccc([N+](=O)[O-])c3)c3c(C)csc3n2)cc1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-5-methyl-thieno-[2,3-d]-pyrimidin-2yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:24][CH2:25][C:26](Cl)=[O:27]>O1CCCC1>[Br:24][CH2:25][C:26]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[C:8]([N+:14]([O-:16])=[O:15])[CH:7]=2)[C:2]([CH3:17])([CH3:1])[CH2:3][CH2:4]1)=[O:27]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCCC2(C)C
Reactant: O=C(Cl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
4,4-dimethyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (1.32 g, 5.59 mmol) was dissolved in tetrahydrofuran (50 mL). This solution was treated with potassium carbonate (1.54 g, 11.2 mmol, Aldrich) and cooled to 0° C. Bromoacetyl chloride (0.93 mL, 11 mmol, Fluka) was added (white precipitation observed) and the reaction stirred for 15 min. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 1-(bromoacetyl)-4,4-dimethyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (assumed 5.59 mmol, 100%). This material was analyzed by 1H NMR (amide rotomers were observed) and taken to bromide displacement reactions directly without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 6 H), 1.75-1.86 (m, 2 H), 3.72-3.82 (m, 2 H), 3.95 (s, 3 H), 4.31-4.69 (two singles at 4.37 and 4.63, 2 H), 7.27 (s, 1 H), 8.28 (very broad singlet, 1 H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([NH2:15])=[N:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OCC)(=[O:19])[C:17]#[CH:18]>C(O)C>[CH2:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]2=[N:15][C:16](=[O:19])[CH:17]=[CH:18][N:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(=O)OCC
Reactant: NC1=NC[C@@H](COCc2ccccc2)O1
Solvent: CCO
Product: O=c1ccn2c(n1)O[C@H](COCc1ccccc1)C2
Temperature: 25 °C
Yield: 27.5 %

Procedure:
To a solution of (S)-5-(benzyloxymethyl)-(4,5-dihydro-oxazol-2-yl)amine (6.02 g, 29.4 mmol) in ethanol (210 mL) was added ethyl propiolate (2.97 mL, 29.4 mmol). The reaction mixture was stirred at reflux for 2.5 hours. The mixture was cooled to room temperature, concentrated under vacuum and purified by column chromatography on silica gel (4:1 ethyl acetate:heptanes to 10% methanol in dichloromethane) to provide 2.09 g (28%) of the title compound. [α]D25 −30.09 (c 0.545, CHCl3).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]1(B2OC(C)(C)C(C)(C)O2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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.O>[C:9]1([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: Nc1ncccc1Br
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncccc1C1=CCCCC1
Yield: 96.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using 3-bromopyridin-2-amine (0.42 g, 2.40 mmol), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.50 g, 2.40 mmol), tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12 mmol), cesium carbonate (1.72 g, 5.29 mmol), 1,4-dioxane (8.0 mL) and water (4.0 mL), to yield the title compound (403.3 mg, 96%) as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:28](#[N:31])[CH:29]=[CH2:30].Cl>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:30][CH2:29][C:28]#[N:31])=[O:15])[CH3:14]
Reactant: CCOP([O-])CCCCc1ccccc1
Reactant: C=CC#N
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(CCC#N)CCCCc1ccccc1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.5 g, 0.0022 mole) in chloroform (10 ml) was added triethylamine (0.341 ml, 0.0024 mole), trimethyl silylchloride (0.303 ml, 0.0024 mole) and acrylonitrile (0.17 ml, 0.0024 mole). The reaction mixture was stirred at reflux temperature for 18 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 10% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with ethyl acetate. The combined organic phase was washed with water, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a thick oil (0.6 g, 97% yield).
Reaction SMILES: [CH2:1]([Si:9]([CH3:14])([CH3:13])N(C)C)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:15][C:16]([F:29])([F:28])[S:17]([O:20]S(C(F)(F)F)(=O)=O)(=[O:19])=[O:18]>>[F:15][C:16]([F:29])([F:28])[S:17]([O:20][Si:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH3:14])[CH3:13])(=[O:19])=[O:18]
Reactant: CCCCCCCC[Si](C)(C)N(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: CCCCCCCC[Si](C)(C)OS(=O)(=O)C(F)(F)F

Procedure:
Additionally, for example when mixing octyldimethyl(dimethylamino)silane as the silicon compound B and trifluoromethanesulfonic anhydride as the acid B, the trifluoromethanesulfonic anhydride is rapidly reacted to form octyldimethylsilyl trifluoromethanesulfonate as the acid A.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.[Br:25]N1C(=O)CCC1=O>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[C:22]([Br:25])[CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a 2 dram vial was added 0.20 g (0.6 mmol) 4-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine, 6.0 mL CH2Cl2, and 104 mg (0.6 mmol) N-bromosuccinimide. The reaction was stirred for 30 min at rt and then quenched with 1 M Na2SO3. The organic layer was separated, dried, and concentrated in vacuo. The deep red product was purified by MPLC to give 0.059 g (24% yield) of a clear, tacky liquid. MS (APCI): 419 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:20](Cl)(=[O:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18].CCN(C(C)C)C(C)C.[CH:33]([O:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)([CH3:35])[CH3:34]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:20]([NH:41][C:40]2[CH:39]=[CH:38][C:37]([O:36][CH:33]([CH3:35])[CH3:34])=[CH:43][CH:42]=2)(=[O:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18]
Reactant: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)Cl)cc2Cl)c(Cl)c1
Reactant: CC(C)Oc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(NS(=O)(=O)c2cc(Cl)c(Oc3ccc([N+](=O)[O-])cc3Cl)c(Cl)c2)cc1
Temperature: 40 °C
Yield: 63 %

Procedure:
To 100 mg of 3,5-Dichloro-4-(2-Chloro-4-Nitrophenoxy)Benzene-1-Sulfonyl Chloride (0.23 m.mol) was added 0.2 ml of DIEA, 5 ml of dichloromethane and 150 mg of 4-isopropoxyaniline. The mixture was maintained at 40° C. for 4 hours. The solvent was evaporated and the residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and the solvent evaporated. The residue as purified using radial silica-gel chromatography using 1:4 ethyl acetate:hexane as solvent. The purity of the product by LC/MS was 97.19%. M−1 (530) was seen in the mass spectrum. The yield of the product was 80.3 mg or 63% yield.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].[CH:27]([C:29]1[CH:47]=[CH:46][C:32]([O:33][CH2:34][C:35]([NH:38]C(=O)OC(C)(C)C)([CH3:37])[CH3:36])=[CH:31][CH:30]=1)=O>>[NH2:38][C:35]([CH3:36])([CH3:37])[CH2:34][O:33][C:32]1[CH:31]=[CH:30][C:29]([CH2:27][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C@@H:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:47][CH:46]=1
Reactant: CC(C)(COc1ccc(C=O)cc1)NC(=O)OC(C)(C)C
Reactant: CCNc1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CC(C)(N)COc1ccc(CCCNc2ccccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 29 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylaminophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and tert-butyl [2-(4-formylphenoxy)-1,1-dimethylethyl]carbamate (125 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (11 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[OH:15][C:16]1[CH:17]=[C:18]([C:22]([CH3:30])([CH2:28][CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:19]=[CH:20][CH:21]=1>>[CH3:30][C:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]3)[CH:17]=1)([CH2:28][CH3:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(C)(CC)c1cccc(O)c1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: CCOC(=O)C(C)(CC)c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Yield: 44 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with ethyl 2-(3-hydroxyphenyl)-2-methylbutyrate to give ethyl 2-methyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyrate in 44% yield as a gum.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13](=[O:30])[CH2:14][C@H:15]([NH:26]C(=O)O)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=2[F:25])[CH2:4][C:3]1=[O:31].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:26][C@H:15]([CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25])[CH2:14][C:13]([N:5]1[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:31])[CH2:4]1)=[O:30]
Reactant: CN1C(=O)CN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)O)Cc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CN(C(=O)C[C@H](N)Cc2cc(F)c(F)cc2F)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 2 [3-(1-methyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-3-oxo-(R)-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tart-butyl ester (90 mg 0.18 mmol) in dry DCM (5 mL), was added trifluoroacetic acid (0.55 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for 1 h. After completion of the reaction, as confirmed by TLC, excess of TFA and DCM were evaporated in vacuo to afford a gummy solid which was crystallised from hexane to afford trifluoroacetic acid salt of 4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-1-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (70 mg, 76%) as a white solid
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[I:10].C([Mg]Cl)(C)C.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[NH4+].[Cl-]>C1COCC1.CCOCC>[I:10][C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[B:16]([OH:21])[OH:17]
Reactant: Cc1cc(C)c(I)c(I)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)c(I)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2-diiodo-3,5-dimethylbenzene (0.5 g, 1.40 mmol) in 60 mL in a mixture of THF and Et2O (1:1), was added dropwise at −78° C. isopropylmagnesium chloride (2 M in THF, 0.70 mL, 1.40 mmol). After the mixture was stirred for 2 h at −78° C., B(OiPr)3 (0.96 ml, 4.19 mmol) was added. The solution was warmed to room temperature overnight, then a saturated solution of NH4Cl was added, and the resulting mixture was stirred for 30 min at room temperature. The aqueous layer was extracted with Et2O (50 mL, 3 times), dried over Na2SO4 and concentrated. To the concentrated sample, hexane was added and the resulting precipitate was isolated to provide the products as shown above as non separable mixture.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1([C:33]2[N:34]=[CH:35][C:36]([C:39](O)=[O:40])=[N:37][CH:38]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:39]([C:36]3[CH:35]=[N:34][C:33]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:38][N:37]=3)=[O:40])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1cnc(N2CCOCC2)cn1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1cnc(N2CCOCC2)cn1

Procedure:
The title compound, off-white solid (95 mg, 73%), MS (ISP) m/z=518.4 [(M+H)+], mp 202° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 5-morpholin-4-yl-pyrazine-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43]([CH3:46])([OH:45])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1.[H-].[K+].[CH3:49][N:50]([CH3:54])[C:51](Cl)=[O:52].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43]([O:45][C:51](=[O:52])[N:50]([CH3:54])[CH3:49])([CH3:46])[CH3:44])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)(C)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)(C)OC(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 1 h

Procedure:
To a solution of 120 mg of 1-[(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2-methyl-propan-2-ol (from example 57b) in 0.5 ml of tetrahydrofuran are added 80 mg potassium hydride (35% dispersion in oil). The reaction mixture is stirred for 1 hour and then 163 μl dimethylcarbamoyl chloride are added. The mixture is stirred at room temperature for 18 hours. The mixture is treated with 2 ml water and extracted with 50 ml ethyl acetate (2×). The combined organic layers are washed with brine and dried with sodium sulfate. The organic layer is filtered and evaporated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow solid. Rf=0.45 (EtOAc-heptane 2:1); Rt=5.59.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:14]1[O:18][C:17]([CH2:19][CH2:20][NH:21][C:22]([NH:24][C:25]2[S:26][C:27]([C:31]3[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([S:38]([CH3:40])=[O:39])[N:32]=3)=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:16][CH:15]=1)[CH3:13]>ClCCl>[CH2:12]([C:14]1[O:18][C:17]([CH2:19][CH2:20][NH:21][C:22]([NH:24][C:25]2[S:26][C:27]([C:31]3[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([S:38]([CH3:40])(=[O:6])=[O:39])[N:32]=3)=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:16][CH:15]=1)[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)=O)n3)s2)o1
Solvent: ClCCl
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)(=O)=O)n3)s2)o1

Procedure:
Meta-chloroperoxybenzoic acid or m-CPBA (57-86% purity, 0.438 g, 1.8 mmol) is added in portions to a rapidly stirring solution of 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methane-sulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (0.31 g, 0.74 mmol) in dry dichloromethane (5 ml) at room temperature. After 2 hours the mixture is diluted with dichloromethane and washed with aqueous sodium thiosulfite and brine. The organic extract is separated, dried over MgSO4 and the solvent is removed. Purification by chromatography on silica, eluting with EtOAc, MeOH (97:3) affords the titled compound.
Reaction SMILES: P(O[CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)(OCC)(OCC)=O.[C:21]([O:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([O:37][C:38](=[O:40])[CH3:39])[C:32]=1[O:33][C:34](=[O:36])[CH3:35])[CH:28]=O)(=[O:23])[CH3:22]>>[CH3:20][O:19][C:13]1[CH:12]=[C:11](/[CH:10]=[CH:28]/[C:27]2[CH:26]=[C:25]([O:24][C:21](=[O:23])[CH3:22])[C:32]([O:33][C:34](=[O:36])[CH3:35])=[C:31]([O:37][C:38](=[O:40])[CH3:39])[CH:30]=2)[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=1
Reactant: CCOP(=O)(OCC)OCc1cc(OC)cc(OC)c1
Reactant: CC(=O)Oc1cc(C=O)cc(OC(C)=O)c1OC(C)=O
Product: COc1cc(/C=C/c2cc(OC(C)=O)c(OC(C)=O)c(OC(C)=O)c2)cc(OC)c1
Yield: 75 %

Procedure:
Use diethyl 3,5-dimethoxybenzyl phosphate and 3,4,5-triacetoxybenzaldehyde as materials, and follow the method described in Example 5 to obtain a white solid as the target product (75%). 1H NMR (400 MHz, DMSO-d6): 2.08 (s, 9H), 3.77 (s, 6H), 6.22 (s, 1H), 6.84 (s, 2H), 6.91 (d, J=16.0 Hz, 1H), 6.92 (d, J=16.0 Hz, 1H), 7.01 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10](=O)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[N:6][CH:7]=1.Cl.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29].N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:8]2[N:28]([C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[F:20])[N:29]=[C:10]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:9]2)[CH:3]=1
Reactant: NNc1ccc(F)cc1F
Reactant: O=C(C=Cc1cncc(Br)c1)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cncc(Br)c2)c(F)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
1-(5-Bromo-pyridin-3-yl)-4,4,5,5,5-pentafluoro-pent-1-en-3-one (2.9 g, 8.6 mmol) prepared in Step 3, 2,4-difluorophenylhydrazine hydrochloride (2.4 g, 8.6 mmol), and piperidine (1.7 mL, 17.3 mmol) were added to ethanol (86.4 mL). The reaction mixture was stirred at 90° C. for 18 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to give 2.4 g of the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:21][CH2:22][CH2:23][O:24][CH3:25])[N:3]=1.[N+:26]([O-])([OH:28])=[O:27]>OS(O)(=O)=O>[Cl:1][C:2]1[C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:21][CH2:22][CH2:23][O:24][CH3:25])[N:3]=1
Reactant: COCCOc1nc(Cl)ccc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COCCOc1nc(Cl)c([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The sub-title compound is prepared from 6-chloro-2-(2-methoxy-ethoxy)-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (2.20 g, 5.78 mmol), fuming HNO3 (5 mL) and conc. H2SO4 (10 mL) in analogy to example 1c.