Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:31]([F:34])([F:33])[F:32])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:30])[CH2:24][N:23]([C:25](=O)[CH:26]([CH3:28])[CH3:27])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:31]([F:34])([F:33])[F:32])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:30])[CH2:24][N:23]([C:25](=[S:44])[CH:26]([CH3:28])[CH3:27])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: CC(C)C(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)C(=S)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidin-1-yl)-2-methylpropan-1-one (500 mg, 1.9 mmol) was dissolved in toluene (35 mL). Lawesson's reagent (790 mg, 1.9 mmol) was added and the reaction mixture was heated to reflux for 2 hours, then cooled to room temperature and allowed to stir overnight. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The crude residue from the filtrate was chromatographed (40 g Redi-Sep column) eluting from 100% heptane to 25:75 EtOAc:heptane to afford the product (415 mg, 80%) as a solid. 1HNMR (CDCl3): 7.77 (2H), 7.61 (2H), 7.54 (2H), 4.68 (4H), 4.12 (1H), 3.72 (1H), 2.88 (1H), 1.28 (6H); m/z (Cl) 537 ([M+H]+.
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7]([CH:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](OCC)=[NH:24])=[CH:17][CH:16]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8])[CH3:5].[CH2:28](N)[CH2:29][NH2:30].Cl>O>[CH2:13]([O:12][C:10]([CH:9]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[NH:24][CH2:28][CH2:29][N:30]=2)=[CH:19][CH:20]=1)[C:7]([O:6][CH2:4][CH3:5])=[O:8])=[O:11])[CH3:14]
Reactant: CCOC(=N)COc1ccc(C(C(=O)OCC)C(=O)OCC)cc1
Reactant: NCCN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OCC2=NCCN2)cc1
Yield: 54.8 %

Procedure:
With ice cooling and stirring, 40 ml of ethanol solution containing 3.6 g of ethyl 2-ethoxycarbonyl-2-[4-(2-ethoxy-2-iminoethoxy]phenyl]acetate obtained in the above step b) was added dropwise to a 10 ml ethanol solution containing 0.6 g of ethylenediamine, and the resulting mixture was stirred at room temperature for 1.5 hours, followed by refluxing under heating for 0.5 hours. After cooling, the resulting reaction solution was adjusted to an acidic pH with ethanol containing 13% (w/v) of hydrochloric acid, and then concentrated to dryness. The residue thus obtained was dissolved in water and washed with diethyl ether. Thereafter, the resulting water layer was adjusted to pH 9-10 with dilute sodium hydroxide aqueous solution, and crystals thus precipitated were collected by filtration. In this way, 1.83 g of the title compound was obtained in the form of colorless crystals.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2.[N:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26][CH:25]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([C:28]3[CH:29]=[N:24][CH:25]=[N:26][CH:27]=3)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(-c2cncnc2)c1
Yield: 32.8 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (150 mg, 0.389 mmol), pyrimidine-5-boronic acid (75.9 mg, 0.613 mmol) and tris(dibenzylideneacetone)dipalladium(0) gave the title compound as a white solid (49 mg, 31%). 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.92 (s, 2H), 7.55-7.41 (m, 2H), 7.19 (dd, J=8.7, 9.9 Hz, 1H), 5.37 (s, 1H), 4.72-4.49 (m, 1H), 3.34-2.04 (m, 6H), 2.04-0.98 (m, 5H), 1.66 (t, J=10.9 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3) δ 159.9, 157.9, 157.4, 156.6, 154.7, 130.2, 127.85, 127.77, 126.9, 122.0, 121.8, 116.7, 116.5, 116.2, 71.6, 55.9, 54.9, 47.6, 46.7, 30.3, 29.6, 25.6, 24.8, 19.8 ppm. Purity: 93% UPLCMS (210 nm); retention time 0.63 min; (M+1) 384.9
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.Br[C:20]1[S:21][CH:22]=[C:23]([Br:25])[CH:24]=1>>[Br:25][C:23]1[CH:24]=[C:20]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:18])[N:3]=2)[S:21][CH:22]=1
Reactant: Brc1csc(Br)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(Br)cs2)n1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example A.31) (4.0 g, 9.36 mmol) and commercially available 2,4-dibromothiophene (2.518 g, 10.41 mmol) according to the general procedure IVc protocol b. Obtained as a white solid (2.12 g, 54%). MS (ISP) 398.0 [(M+H)+] and 400.0 [(M+2+H)+].
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23]C([O-])(C)C.[K+].CI>C1COCC1>[CH:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH3:23])[CH:15]=3)[CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)[O-]
Reactant: c1cnc2[nH]cc(-c3ccnc(NC4CCCCC4)n3)c2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1cc(-c2ccnc(NC3CCCCC3)n2)c2cccnc21
Reaction time: 1 h
Yield: 82 %

Procedure:
Compound 13 (24 mg) was dissolved in THF (1 mL) and KOtBu (1 M in THF, 82 μL) was added. The mixture was stirred for 1 hr, followed by addition of methyl iodide (5.1 μL). The stirring was continued for additional 1 hr, then the solution was concentrated and the residue was purified by flash chromatography [silica gel, EtOAc] to afford 16 mg (82%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 8.65 (d, 1 H), 8.32 (d, 1 H), 8.13 (d, 1 H), 7.75 (s, 1 H), 7.15 (dd, 1 H), 6.71 (d, 1 H), 5.0 (m, 1 H), 3.90 (s, 3 H), 3.88 (m, 1 H), 2.10 (m, 2 H), 1.70 (m, 2 H), 1.60 (m, 2 H), 1.40 (m, 2 H), 1.20 (m, 2 H). MS (ESI) m/z: 308 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:25])[CH:5]=[CH:4][C:3]=1[OH:26].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)CCCCBr
Reactant: Cc1cc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1O
Product: COC(=O)CCCCOc1ccc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
Prepared in an analogous manner to example 11 from intermediate 7 and methyl 5-bromopentanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([C:7](=[O:14])[CH2:8][O:9][CH2:10]2)=[CH:5][CH:4]=1.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18].C[O-].[Na+].CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([F:13])=[C:11]2[C:6]([C:7](=[O:14])[CH:8]([C:17](=[O:18])[C:16]([F:23])([F:22])[F:15])[O:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc2c(c1F)COCC2=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1F)COC(C(=O)C(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A solution of 7-methoxy-8-fluoroisochroman-4-one from Step 2 (370 mg, 1.76 mmol) and ethyl trifluoroacetate (290 mg, 2.04 mmol) in 8 mL of anhydrous tetrahydrofuran was treated with a solution of 25% sodium methoxide in methanol (570 mg, 2.64 mmol). The solution was stirred at room temperature for 16 hours, treated with excess 3N hydrochloric acid, and extracted with ether. The ethereal extract was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 450 mg (88%) of pure 7-methoxy-8-fluoro-3-(trifluoroacetyl)isochroman-4-one which was used directly in the next step without further purification.
Reaction SMILES: [N:1]([N+]([O-])=O)=[O:2].[CH2:6]([N:11]([CH:18]([OH:33])[C@H:19]1[O:25][C@:23]([CH2:26][CH2:27][CH2:28][CH3:29])([OH:24])[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32])[C:12](=[O:17])[NH:13][CH2:14][CH2:15][Cl:16])[CH2:7][CH:8]([CH3:10])[CH3:9]>O1CCCC1.C(O)(=O)C>[CH2:6]([N:11]([CH:18]([OH:33])[C@H:19]1[O:25][C@:23]([CH2:26][CH2:27][CH2:28][CH3:29])([OH:24])[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32])[C:12](=[O:17])[N:13]([CH2:14][CH2:15][Cl:16])[N:1]=[O:2])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: O=N[N+](=O)[O-]
Reactant: CCCC[C@]1(O)O[C@H](C(O)N(CCC(C)C)C(=O)NCCCl)[C@@H](O)[C@H](O)[C@H]1O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCC[C@]1(O)O[C@H](C(O)N(CCC(C)C)C(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O
Yield: 60.4 %

Procedure:
Dinitrogen trioxide gas (0.6 g) was introduced into a solution of 3-isopentyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (2.15 g, 5.23 mmol), synthesized in the above-mentioned way, in a mixture of tetrahydrofuran (50 ml) and acetic acid (8 ml) with well stirring at 0° to 5° C. After continuation of stirring for 2 hours, the resulting solution was vacuum-concentrated at 25° C. and purified by column chromatography (packing: Kiesel gel 60; eluent: chloroform/methanol 10:1), giving 1.44 g of 3-isopentyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea; yield 62.6%, m.p. 66°-68° C., [α]D20 +65.2° (C 1.0, methanol).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([NH2:24])=[N:20]1>>[F:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[CH:22][C:21]([NH:24][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([CH3:1])[N:6]=3)[CH2:8][CH2:9]2)=[N:20]1
Reactant: Nc1ccn(Cc2cccc(F)c2)n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3ccn(Cc4cccc(F)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3-fluoro-benzyl)-1H-pyrazol-3-ylamine. The title compound was obtained as a yellow oil (yield=73%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])=[CH:13][CH:12]=1.Cl[C:25]([O:27][CH3:28])=[O:26]>C(Cl)Cl>[O:23]=[C:18]1[CH2:19][O:20][CH2:21][CH2:22][N:17]1[C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:25](=[O:26])[O:27][CH3:28])=[CH:16][CH:15]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
N,N-Diisopropylethylamine (27.2 mL, 156.08 mmol) was added over 3 min to a stirred suspension of 4-(4-aminophenyl)-3-morpholinone (2, 25 g, 130.07 mmol) in CH2Cl2 (750 mL). The reaction mixture was stirred at room temperature for 15 min and methyl chloroformate (11.6 mL, 149.58 mmol) was added drop-wise over 10 min. The resulting thick suspension was stirred for another 1 h and filtered through a Buchner funnel. The solid was washed with CH2Cl2 (2×75 mL) and dried under vacuum to obtain methyl N-[4-(3-oxo-4-morpholinyl)phenyl]carbamate (5b, 30.92 g, 95%) as a crystalline solid.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8](=O)(OCC)[O:9]CC.C[O-].[Na+]>>[OH:4][CH2:3][CH2:2][N:1]1[CH2:5][CH2:6][O:7][C:8]1=[O:9]
Reactant: CCOC(=O)OCC
Reactant: OCCNCCO
Agent: C[O-]
Agent: [Na+]
Product: O=C1OCCN1CCO

Procedure:
A mixture of diethanolamine (12.55 g), diethyl carbonate (16.2 mL), and sodium methoxide (80 mg) was heated to 130–140° C. for 1.5 h and distilled during the reaction using a Dean-Stark trap. The remaining liquid was concentrated in vacuo to give 15.11 g (97%) as a yellow oil.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:17]>CN(C=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.5 %

Procedure:
tert-Butyl piperazine-1-carboxylate (5.00 g, 26.8 mmol) and 2-bromo-1-(4-fluorophenyl)ethanone (6.99 g, 32.2 mmol) were dissolved in DMF (5 mL) and stirred for 10 min at room temperature. The crude material was purified by column chromatography eluting with a mixture of DCM and MeOH to afford the title compound (3.50 g) as an oil. 1H NMR (Acetonitrile-d3, 400 MHz) δ 1.42 (s, 9H) 2.47 (t, J=5.0 Hz, 4H), 3.36 (t, J=5.0 Hz, 4H), 3.77 (s, 2H), 7.20 (t, J=8.8, 2H), 8.07 (td, J=2.0, 8.8 Hz, 2H). Exact mass calculated for C17H23FN2O3: 322.2. Found: LCMS m/z=323.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:10]=3[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40]([O:43][CH2:44][C:45](Cl)=[O:46])(=[O:42])[CH3:41]>ClCCl>[C:40]([O:43][CH2:44][C:45]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:10]=3[N:11]([CH3:27])[C:12](=[O:26])[CH:13]([CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[N:14]=2)=[CH:6][N:7]=1)=[O:46])(=[O:42])[CH3:41]
Reactant: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(c2ccc(N)nc2)c2cc(Cl)ccc21
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc(C2=NC(Cc3ccc4ccccc4c3)C(=O)N(C)c3ccc(Cl)cc32)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
5-(6-Aminopyridin-3-yl)-7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (50 mg, 0.11 mmol) was dissolved in dichloromethane (0.5 mL), and triethylamine (19 μL, 0.14 mmol) was added followed by acetoxyacetyl chloride (13 μL, 0.12 mmol). A slightly exothermic reaction occurred. This mixture as stirred at ambient temperature overnight. Additional triethylamine (46 μL, 0.33 mmol) was added followed by acetoxyacetyl chloride (30 μL, 0.22 mmol) and stirring continued at ambient temperature for 4 days. Concentration in the presence of silica, then column chromatography eluting with a step gradient of 20-80% ethyl acetate in hexanes in 5% increments every 3 minutes provided 2-(5-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)pyridin-2-ylamino)-2-oxoethyl acetate (45 mg, 73%). 1H NMR (300 MHz, d6-DMSO) δ 2.10 (s, 3H), 3.3 (s, 3H), 3.53 (d, 2H) 3.83 (t, 1H), 4.72 (s, 2H), 7.30 (m, 1H), 7.4-7.5 (m, 3H), 7.60 (m, 2H), 7.65 (m, 1H), 7.77-7.88 (m, 4H), 8.03 (m, 1H), 8.36, (m, 1H), 10.94 (s, 1H); ESI m/z measured 541.1646 [M+H]+. calculated 541.1643.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH:17]([CH:19]=O)=[O:18].Cl>C(O)(=O)C>[C:1]([C:5]1[C:10]2[O:11][C:17](=[O:18])[CH2:19][C:9]=2[CH:8]=[C:7]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC=O
Reactant: CC(C)(C)c1cc(CCC(=O)O)ccc1O
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(CCC(=O)O)cc2c1OC(=O)C2
Temperature: 0 °C

Procedure:
66.7 g (0.3 mol) of 3-(3-tert-butyl-4-hydroxy-phenyl)-propionic acid (prepared analogously to the method described in JP-A2-63/227542) in 58 g (0.4 mol) of aqueous glyoxal solution (40% by weight) and 3 ml of hydrochloric acid (32% by weight) are heated at reflux in 200 ml of acetic acid for 6 hours. The mixture is then poured into 600 ml of ice-water and the precipitate is filtered off. The filter residue is washed with water and then dried at 60° C. g. Recrystallisation from toluene results in 54.3 g (69% of theory) of 3-(7-tert-butyl-2-oxo-2,3-dihydro-benzofuran-5-yl)-propionic acid. Melting point 167-169° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([C:17]1[CH:26]=[CH:25][C:20]([CH2:21][NH:22][O:23][CH3:24])=[CH:19][CH:18]=1)([O:15][CH3:16])=[O:14]>>[CH3:16][O:15][C:13](=[O:14])[C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]([C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: CONCc1ccc(C(=O)OC)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: COC(=O)c1ccc(CN(OC)C(=O)C=C2OC(C)(C)OC2=O)cc1
Yield: 83 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-4-carbomethoxybenzyl-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as a white solid (83% yield): mp 120° C. (dichloromethane-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.67 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.88 (2H, s, NCH2), 6.40 (1H, s, CH), 7.42 (2H, d, aromatics), 8.0 (2H, d, aromatics). Anal. calcd for C17H19NO7: C, 58.45; H, 5.48; N, 4.01. Found: C, 58.54; H, 5.55; N, 3.61.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8]1)=[O:6])[CH:2]=[CH2:3].[CH3:14]C(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.C(OCC)(=O)C>CC(C)=O>[C:12]([CH:9]1[CH2:10][CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH2:8]1)(=[O:13])[CH3:14]
Reactant: CC(C)=O
Reactant: C=CCOC(=O)N1CCC(CO)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C=CCOC(=O)N1CCC(C(C)=O)C1
Reaction time: 1 h

Procedure:
To a solution of 1-allyloxycarbonyl-3-hydroxymethylpyrrolidine (2.6 g) in acetone was added Jones reagent (1.25N, 20 ml) at ambient temperature. After stirring for 1 hour, isopropyl alcohol (10 ml) was added thereto. The resulting precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in dichloromethane, dicyclohexylcarbodiimide (0.79 g), Meldrum's acid (0.55 g), 4-methylaminopyridine (0.47 g) to the solution at 0° C. After stirring for 24 hours at ambient temperature, the resulting precipitate was removed by filtration. The filtrate was washed with 1N hydrochloric acid and evaporated in vacuo. The residue was dissolved in a mixture of acetic acid (10 ml) and water (7 ml), and the mixture was refluxed for 1 hour. Evaporation of the solvent gave a residue, which was taken up into ethyl acetate. The solution was washed in turn with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1, V/V) to give 3-acetyl-1-allyloxycarbonylpyrrolidine (2.01 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][N:17]([CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: c1ccc(COc2cccc(CCNC3CCOC3)c2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CN(CCc1cccc(OCc2ccccc2)c1)C1CCOC1
Temperature: 120 °C
Yield: 59.4 %

Procedure:
A mixture of 0.8 g (2.69 mmol) of [2-(3-benzyloxy-phenyl)-ethyl]-(tetrahydrofuran-3-yl)amine, 0.56 ml (4.03 mmol) of triethylamine and 0.415 ml (4.03 mmol) of 2-chloro-N,N-dimethyl-acetamide in 5 ml of dry dimethylformamide was heated to 120° C. for 2 hours with microwaves. Solvent was removed under vacuum and the crude residue was purified by flash chromatography (dichloromethane/methanol: 100:3, v:v). 0.611 g (59% yield) of the title compound were isolated as a yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)#[N:29]>>[CH2:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][C:30]([C:28]#[N:29])=[CH:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc2c(c1-c1ccc(C#N)cc1)CCNCC2
Yield: 35.6 %

Procedure:
The title compound (47 mg) was prepared according to Example 193 using 205 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 218 mg of 4-cyanophenylboronic acid. MS (ESI): exact mass calculated for C16H18N4, 266.15. found, m/z 267.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.93-7.91 (m, 2H), 7.58-7.56 (m, 2H), 4.03 (q, J=7.2 Hz, 2H), 3.43-3.40 (m, 2H), 3.18-3.16 (m, 2H), 2.82-2.80 (m, 2H), 1.29 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1.[Br:16][C:17]1[NH:25][C:24]2[C:19](=[N:20][C:21]([Cl:26])=[CH:22][CH:23]=2)[CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[Br:16][C:17]1[N:25]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[C:24]2[C:19](=[N:20][C:21]([Cl:26])=[CH:22][CH:23]=2)[CH:18]=1
Reactant: Clc1ccc2[nH]c(Br)cc2n1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cccc(Cn2c(Br)cc3nc(Cl)ccc32)c1

Procedure:
K2CO3 (0.97 g, 7.0 mmol) and 1-(bromomethyl)-3-chlorobenzene (0.74 mL, 5.6 mmol, Aldrich) were added to a solution of 2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (1.5 g, 4.7 mmol, from Step 1) in DMF (20 mL). After a reaction time of 75 minutes, the reaction was diluted with ethyl acetate and washed with water three times, followed by one wash with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. Flash chromatography, loading in DCM, eluting with a gradient from 0-10% EtOAc in hexanes, afforded product as a white solid. Yield (1.3 g, 70%).
Reaction SMILES: [C:1]1([S:7]([CH:10]([CH:13]2[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]2)[C:11]#[N:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[C:1]1([S:7]([C:10]([CH:13]2[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]2)([CH3:22])[C:11]#[N:12])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)(C1CCCC(=O)C1)S(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 98.1 %

Procedure:
4.0 g (0.014 mol) of benzenesulfonyl-(3-oxo-cyclohexyl)-acetonitrile in 40 mL of DMF were treated with 0.69 g (0.016 mol, 1.1 eq) of NaH (55% in oil) portionwise within 30 min at 0° C. 3.07 g (0.022 mol, 1.5 eq) of methyliodide were added, and the ice bath was removed. After 2 hours, the reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography over silica gel with AcOEt/heptane 1:1 afforded 4 g (98%) of 2-benzenesulfonyl-2-(3-oxo-cyclohexyl)-propionitrile as a racemic mixture of diastereomers, white solid, MS: 292 (MH+).